chr5-147828115-T-C

Position:

• chr5-147828115-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001379610.1(SPINK1):​c.101A>G​(p.Asn34Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,612,638 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,association,risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.0082 (7 hom., cov: 32)
  • Exomes 𝑓: 0.011 (124 hom.)
• Consequence: SPINK1 NM_001379610.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity; association; risk factor criteria provided, conflicting classifications P:18 U:4 B:1 O:5
• Conservation: PhyloP100: -3.75

Genes affected

SPINK1 (HGNC:11244): (serine peptidase inhibitor Kazal type 1) The protein encoded by this gene is a trypsin inhibitor, which is secreted from pancreatic acinar cells into pancreatic juice. It is thought to function in the prevention of trypsin-catalyzed premature activation of zymogens within the pancreas and the pancreatic duct. Mutations in this gene are associated with hereditary pancreatitis and tropical calcific pancreatitis. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005059749).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00825 (1256/152316) while in subpopulation SAS AF= 0.0176 (85/4816). AF 95% confidence interval is 0.0146. There are 7 homozygotes in gnomad4. There are 626 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 1256 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINK1	NM_001379610.1	c.101A>G	p.Asn34Ser	missense_variant	3/4	ENST00000296695.10	NP_001366539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINK1	ENST00000296695.10	c.101A>G	p.Asn34Ser	missense_variant	3/4	1	NM_001379610.1	ENSP00000296695.5
SPINK1	ENST00000510027.2	c.101A>G	p.Asn34Ser	missense_variant	3/3	3		ENSP00000427376.1
SPINK1	ENST00000505722.1	n.16A>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00825 AC: 1256 AN: 152198 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00596

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00906 AC: 2262 AN: 249598 Hom.: 20 AF XY: 0.00989 AC XY: 1334 AN XY: 134900

Gnomad AFR exome AF: 0.00241

Gnomad AMR exome AF: 0.00174

Gnomad ASJ exome AF: 0.000899

Gnomad EAS exome AF: 0.00279

Gnomad SAS exome AF: 0.0198

Gnomad FIN exome AF: 0.0172

Gnomad NFE exome AF: 0.00964

Gnomad OTH exome AF: 0.00772

GnomAD4 exome AF: 0.0113 AC: 16555 AN: 1460322 Hom.: 124 Cov.: 30 AF XY: 0.0117 AC XY: 8486 AN XY: 726450

Gnomad4 AFR exome AF: 0.00123

Gnomad4 AMR exome AF: 0.00212

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.00422

Gnomad4 SAS exome AF: 0.0214

Gnomad4 FIN exome AF: 0.0159

Gnomad4 NFE exome AF: 0.0115

Gnomad4 OTH exome AF: 0.0115

GnomAD4 genome AF: 0.00825 AC: 1256 AN: 152316 Hom.: 7 Cov.: 32 AF XY: 0.00840 AC XY: 626 AN XY: 74484

Gnomad4 AFR AF: 0.00260

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00578

Gnomad4 SAS AF: 0.0176

Gnomad4 FIN AF: 0.0179

Gnomad4 NFE AF: 0.0110

Gnomad4 OTH AF: 0.0113

Alfa AF: 0.00935 Hom.: 35

Bravo AF: 0.00661

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0109 AC: 42

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0109 AC: 94

ExAC AF: 0.00912 AC: 1107

Asia WGS AF: 0.0370 AC: 128 AN: 3478

EpiCase AF: 0.00780

EpiControl AF: 0.00878

ClinVar

Significance: Conflicting classifications of pathogenicity; association; risk factor

Submissions summary: Pathogenic:18 Uncertain:4 Benign:1 Other:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary pancreatitis Pathogenic:13 Uncertain:2 Other:5

association, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2025	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 34 of the SPINK1 protein (p.Asn34Ser). This variant is present in population databases (rs17107315, gnomAD 2.0%), and has an allele count higher than expected for a pathogenic variant. This variant is reported as heterozygous in approximately 12% of individuals affected with chronic pancreatitis and in approximately 1.9% of unaffected controls (PMID: 17466744). Based on this data, this variant is expected to confer an approximate 6-12 fold increased risk for chronic pancreatitis in heterozygous carriers. Homozygous individuals have been reported in approximately 3-5% of individuals with chronic pancreatitis (PMID: 23951356, 10835640), approximately 0.015% of the general population (ExAC), and in no unaffected controls to date (reviewed in PMID: 17466744). Although homozygous individuals are presumed to have at least twice the risk of heterozygous carriers, an accurate odds ratio can not be calculated due to the small number of homozygous individuals in the general population. ClinVar contains an entry for this variant (Variation ID: 13760). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Multiple studies have failed to demonstrate that this Asn34Ser missense change disrupts any known function of the SPINK1 protein (PMID: 12483248, 17568390, 17525091). In summary, this variant is a missense change that does not affect any known function of the SPINK1 protein function. While this variant is associated with a significant risk for developing chronic pancreatitis, in the absence of a deleterious protein effect it remains uncertain whether this variant directly contributes to disease or if it may be linked to an undiscovered mutation (PMID: 19299380). Therefore, it has been classified as an Increased Risk Allele. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	May 24, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 21, 2023	The c.101A>G (p.N34S) alteration is located in exon 3 (coding exon 3) of the SPINK1 gene. This alteration results from an A to G substitution at nucleotide position 101, causing the asparagine (N) at amino acid position 34 to be replaced by a serine (S). Based on data from gnomAD, the G allele has an overall frequency of 0.903% (2537/281004) total alleles studied. The highest observed frequency was 1.975% (602/30476) of South Asian alleles. This mutation has been observed in heterozygous and homozygous states in individuals with chronic pancreatitis (Witt, 2000). In case control studies, p.N34S has has been associated with a significant odds ratio for both acute pancreatitis and chronic pancreatitis (O'Reilly, 2008; Rosendahl, 2013). Heterozygous p.N34S confers an increased risk, while homozygous p.N34S is considered to be disease-causing (Masson, 2013). This amino acid position is poorly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 17, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Undiagnosed Diseases Network, NIH	Nov 17, 2020	- -
Established risk allele, no assertion criteria provided	case-control	Intergen, Intergen Genetics and Rare Diseases Diagnosis Center	Jul 20, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Aug 23, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: BS1,PS4,PS1. This variant was detected in homozygous state. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 08, 2020	SPINK1 c.101A>G (p.Asn34Ser) results in a conservative amino acid change located in the Kazal domain (IPR002350) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.009 in 254072 control chromosomes (gnomAD and publication data), including 20 homozygotes. This frequency is approximately 2 times the estimated maximal expected allele frequency of a pathogenic SPINK1 variant. However, this variant is a well-reported pathogenic risk factor that is known to be relatively frequent in the general population. Multiple studies have identified the variant in the compound heterozygous and homozygous state in numerous patients with chronic pancreatitis (example, Witt_2000, Chandak_2002, Rosendahl_2012, Pelaez-Luna_2014). Large association studies have been performed that suggest a strong association between the variant and disease, with odds ratios ranging from 10 to over 50 (example, Chen_2009, Witt_2000). However, experimental data reported that the trypsin inhibitory activity of the variant protein was preserved (> 90% of normal) and there was no significant difference in mRNA expression or splicing compared to wild-type (Kuwata_2002, Kiraly_2007, Boulling_2012). Although it has been proposed that other cis-linked variant(s) might be responsible for the observed increased pancreatitis risk conferred by the N34S haplotype, studies reporting a causative role of this variant within its associated haplotype have also been reported (Boulling_2012, Boulling_2017, Kereszturi_2017). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as VUS (n=3), Pathogenic (n=4) or Risk factor (n=2)). Based on the evidence outlined above, the variant was classified as a pathogenic risk factor for predisposition to Chronic Pancreatitis. -
Likely risk allele, no assertion criteria provided	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jun 15, 2023	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 34 of the SPINK1 protein (p.Asn34Ser). This variant is present in population databases (rs17107315, gnomAD 2.0%). This variant is reported as heterozygous in ~12% of individuals affected with chronic pancreatitis and in ~1.9% of unaffected controls (PMID: 17466744). Based on this data, this variant is expected to confer ~6-12 fold increased risk for chronic pancreatitis in heterozygous carriers. Homozygous individuals have been reported in approximately 3-5% of individuals with chronic pancreatitis (PMID: 23951356, 10835640), ~0.015% of the general population (ExAC), and in no unaffected controls to date (reviewed in PMID: 17466744). Although homozygous individuals are presumed to have at least twice the risk of heterozygous carriers, an accurate odds ratio can not be calculated due to the small number of homozygous individuals in the general population. ClinVar contains an entry for this variant (Variation ID: 13760). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Multiple studies have failed to demonstrate that this Asn34Ser missense change disrupts any known function of the SPINK1 protein (PMID: 12483248, 17568390, 17525091). In summary, this variant is a missense change that does not affect any known function of the SPINK1 protein function. While this variant is associated with a significant risk for developing chronic pancreatitis, in the absence of a deleterious protein effect it remains uncertain whether this variant directly contributes to disease or if it may be linked to an undiscovered mutation (PMID: 19299380). Therefore, it has been classified as an Increased Risk Allele. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins-Biomnis	Dec 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Nov 02, 2023	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Established risk allele and reported on 01-31-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
risk factor, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 12, 2021	proposed classification - variant undergoing re-assessment, contact laboratory -
Established risk allele, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 08, 2022	One of the most important CP-associated heritable risk factors (odds ratio (OR) = 10.90; 95% confidence interval 7.56–15.72). No functional data support pathogenic effect (expression, secretion or trypsin inhibitory activity of SPINK1). Linked with SNP rs142703147:C>A (c.-4141G>T) in this individual (this variant disrupts a PTF1L-binding site within an evolutionarily conserved HNF1A-PTF1L cis-regulatory module (CRM). Co-transfection transactivation experiments have demonstrated that this variant leads to reduced gene expression. Two pancreatic cancer cell lines heterozygous for the SPINK1 N34S haplotype exhibited reduced expression of the variant allele and suggested that c.-4141G>T might be a candidate causal variant. See Pu et al., 2021, PMID: 34828289 -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The missense c.101A>G(p.Asn34Ser) variant in SPINK1 gene has been reported previously in heterozygous as well as homozygous state in multiple individuals affected with chronic pancreatitis (Witt H et al., 2007). This variant has been reported with the allele frequency of 0.9% in the gnomAD Exomes database. This variant has been submitted to the ClinVar database with Likely Benign / Uncertain Significance / Established risk allele / Likely pathogenic / Pathogenic. Multiple lines of computational evidence (Polyphen - Benign, SIFT - Tolerated and MutationTaster - Polymorphism) predict no damaging effect on protein structure and function for this variant. The amino acid Asn at position 34 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. Though functional studies have not proven a damaging effect, the variant is enriched in patients with pancreatitis as compared to the general population (Király O et al., 2007,Rosendahl J et al. ,2013 ). For these reasons, this variant has been classified as a Pathogenic variant which acts as a risk factor for the development of pancreatitis. -

not provided Pathogenic:2 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SPINK1: PP1:Strong, PS1, PS4, PP4:Moderate, BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2017	This variant is denoted SPINK1 c.101A>G at the cDNA level, p.Asn34Ser (N34S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant is associated with an increased risk of pancreatitis when present with other genetic or environmental risk factors (Witt 2000, Diaconu 2009, Masamune 2011, LaSaito 2016). In a meta-analysis, this variant was identified in the heterozygous state in 274/2927 Caucasian pancreatitis cases and 79/5298 controls (OR=6.82), and in the homozygous state in 54/2981 cases and 1/5299 controls (OR=97.74) (Di Leo 2017). Functional studies of SPINK1 N34S demonstrated no change in trypsin inhibition or binding activity, suggesting that SPINK1 N34S on its own is insufficient to cause pancreatitis (Kuwata 2002, Boulling 2007). SPINK1 Asn34Ser is the most common SPINK1 pancreatitis risk allele, with an allele frequency of 0.97% (590/60648) and 2.2% (332/15160) in individuals of European (non-Finnish) and South Asian ancestry, respectively, in large population cohorts (Lek 2016). This variant is located in the Kazal-like domain (UniProt). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, we consider SPINK1 Asn34Ser to be a risk allele. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	The SPINK1 c.101A>G; p.Asn34Ser variant (rs17107315) has been detected at a statistically significant increased frequency in individuals with pancreatitis as compared to the general population (Aoun 2010, Masson 2013, Rosendahl 2013), co-segregating with pancreatitis patients in multiple families (Wu 2022). This variant and its associated haplotype is a risk factor for developing pancreatitis when combined with an additional pathogenic SPINK1 variant on the opposite chromosome, a severe pathogenic CFTR gene variant, or a pathogenic CTRC gene variant (Boulling 2017, Rosendahl 2013, Zou 2018). The p.Asn34Ser variant is reported in ClinVar (Variation ID: 13760). This variant is found in the general population with an overall allele frequency of 0.9% (2537/281004 alleles, 23 homozygotes) in the Genome Aggregation Database. The asparagine at codon 34 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.199). Based on this variant's strong association with pancreatitis, we consider it pathogenic. References: Aoun E et al. SPINK1 N34S is strongly associated with recurrent acute pancreatitis but is not a risk factor for the first or sentinel acute pancreatitis event. Am J Gastroenterol. 2010 105(2):446-51. PMID: 19888199. Boulling A et al. Identification of a functional enhancer variant within the chronic pancreatitis-associated SPINK1 c.101A>G (p.Asn34Ser)-containing haplotype. Hum Mutat. 2017 Aug;38(8):1014-1024. PMID: 28556356. Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013 8(8):e73522. PMID: 23951356. Rosendahl J et al. CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated? Gut. 2013 62(4):582-92. PMID: 22427236. Wu D et al. The clinical and genetic features of hereditary pancreatitis in South Australia. Med J Aust. 2022 Jun 20;216(11):578-582. PMID: 35578795. Zou WB et al. SPINK1, PRSS1, CTRC, and CFTR Genotypes Influence Disease Onset and Clinical Outcomes in Chronic Pancreatitis. Clin Transl Gastroenterol. 2018 Nov 12;9(11):204. PMID: 30420730. -

Tropical pancreatitis Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed in the gnomAD v2.1.1 ( https://gnomad.broadinstitute.org ) dataset at total allele frequency of 0.903%. Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with SPINK1 -related disorder (ClinVar ID: VCV000013760 / PMID: 10835640 / 3billion dataset). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 22427236). It has been reported to co-segregate with the disease in at least 5 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 11950815 , 12187509). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 17, 2022	- -

Pancreatitis Pathogenic:1

Likely risk allele, no assertion criteria provided

research

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The SPINK1 c.101A>G (p.Asn34Ser) variant is a commonly reported risk variant associated with pancreatitis and has been reported in >300 affected individuals, as well as in >100 unaffected controls (Di Leo_2017_PMID: 28546062; Diaconu_2009_PMID: 19565042; Masamune_2011_PMID: 21303407; Chandak_2002_PMID: 12011155; Rosendahl_2013_PMID: 22427236; Witt_2000_PMID: 10835640). In a large meta-analysis, this variant has a reported odds ratio of 9.695 (CI 95% 7.931–11.851) in pancreatitis cases vs controls (Di Leo_2017_PMID: 28546062). The variant was identified in dbSNP (ID: rs17107315) and ClinVar (classified as pathogenic by Ambry Genetics and 8 other submitters; as uncertain significance by GeneDx and 4 other submitters; as "risk factor" by Laboratory for Molecular Medicine; and as "association" by Invitae). The variant was identified in control databases in 2537 of 281004 chromosomes (23 homozygous) at a frequency of 0.009028, and was observed at the highest frequency in the South Asian population in 602 of 30476 chromosomes (freq: 0.01975) (Genome Aggregation Database March 6, 2019, v2.1.1). The p.Asn34 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) provide inconsistent predictions regarding the impact to the protein. Three in vitro functional studies have demonstrated that this variant does not affect protein expression or trypsin inhibitory activity (Kuwata_2002_PMID: 12483248; Boulling_2007_PMID: 17568390; Kiraly_2007_PMID: 17525091). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. However, this variant may act as a risk factor for pancreatitis. -

Pancreatitis, chronic, susceptibility to Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Oct 01, 2002

- -

Finnish congenital nephrotic syndrome Benign:1

Likely benign, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

-

The p.Asn34Ser variant in SPINK1 has been reported in 12 heterozygous and 6 homozygous individuals with chronic pancreatitis (PMID: 10835640). It has also been identified in >0.1% of chromosomes, including 9 homozygotes, by ExAC (http://gnomad.broadinstitute.org/). In vitro functional studies provide some evidence that this variant does not impact protein function (PMID: 12483248, 17568390, 17525091). However, these types of assays may not accurately represent biological function. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal dominant chronic pancreatitis. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.0010
DANN	Benign	0.17
DEOGEN2	Benign	0.081	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.42	T;T
MetaRNN	Benign	0.0051	T;T
MetaSVM	Benign	-0.93	T
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.68	N;N
REVEL	Benign	0.20
Sift	Benign	0.42	T;T
Sift4G	Benign	0.78	T;T
Polyphen		0.010	B;.
Vest4		0.053
MVP		0.43
MPC		0.018
ClinPred		0.0019	T
GERP RS		-3.9
Varity_R		0.098
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs17107315; hg19: chr5-147207678; COSMIC: COSV99031471;