5-147824701-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001379610.1(SPINK1):c.200G>A(p.Arg67His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,613,846 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R67C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0096 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (29 hom.)
• Consequence: SPINK1 NM_001379610.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:9
• Conservation: PhyloP100: 0.0970

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005965978).
• BP6: Variant 5-147824701-C-T is Benign according to our data. Variant chr5-147824701-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 132716.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Likely_benign=4, Uncertain_significance=1}. Variant chr5-147824701-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0096 (1461/152150) while in subpopulation AFR AF= 0.0315 (1307/41514). AF 95% confidence interval is 0.0301. There are 13 homozygotes in gnomad4. There are 706 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1454 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPINK1	NM_001379610.1	c.200G>A	p.Arg67His	missense_variant	4/4	ENST00000296695.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPINK1	ENST00000296695.10	c.200G>A	p.Arg67His	missense_variant	4/4	1	NM_001379610.1	P1
SPINK1	ENST00000505722.1	n.115G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00956 AC: 1454 AN: 152032 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.0314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00675

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00957

GnomAD3 exomes AF: 0.00256 AC: 640 AN: 250356 Hom.: 10 AF XY: 0.00182 AC XY: 247 AN XY: 135376

Gnomad AFR exome AF: 0.0318

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000292

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00117 AC: 1711 AN: 1461696 Hom.: 29 Cov.: 31 AF XY: 0.00104 AC XY: 755 AN XY: 727148

Gnomad4 AFR exome AF: 0.0344

Gnomad4 AMR exome AF: 0.00257

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000255

Gnomad4 OTH exome AF: 0.00232

GnomAD4 genome AF: 0.00960 AC: 1461 AN: 152150 Hom.: 13 Cov.: 32 AF XY: 0.00949 AC XY: 706 AN XY: 74382

Gnomad4 AFR AF: 0.0315

Gnomad4 AMR AF: 0.00674

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00947

Alfa AF: 0.00221 Hom.: 9

Bravo AF: 0.0108

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0334 AC: 147

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00305 AC: 370

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary pancreatitis Benign:6

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 28, 2015	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 21, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2024	- -

not provided Uncertain:3 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 18, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 24, 2023	BP4, PM5 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 16, 2021

Variant summary: SPINK1 c.200G>A (p.Arg67His) results in a non-conservative amino acid change located in the Kazal domain (IPR002350) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0054 in 433772 control chromosomes, predominantly at a frequency of 0.031 within the African or African-American subpopulation in the gnomAD database (v2.1 and v3), including 22 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 124 fold of the estimated maximal expected allele frequency for a pathogenic variant in SPINK1 causing Chronic Pancreatitis phenotype (0.00025). However, this subpopulation frequency (0.031) is only slightly higher than the maximal expected allele frequency of a recessive CPANC pathogenic SPINK1 allele (0.022). Recent research studies suggest that at least one third of recurrent acute and chronic pancreatitis results from complex genetic mechanisms (Whitcomb, NAPS2 study 2014, unpublished; GeneReviews), commonly complex multi-gene variants in SPINK1/CFTR. The majority of kindreds with familial pancreatitis without risk associated with a single locus (e.g., PRSS1, CFTR, or SPINK1) are small, with two to four affected individuals. These families and simplex cases (i.e. a single occurrence in a family) are increasingly found to have complex, multi-genic, or gene-environmental disorders with a variable number of germline pathogenic variants in genes that affect trypsin regulation. Therefore, it is difficult to establish the mode of inheritance or an accurate estimate of the maximal expected allele frequency for pathogenic SPINK1 variants. Additionally, in the United States, Europe, and India, a high-risk haplotype containing SPINK1 p.Asn34Ser (NM_003122.3:c.101A>G) is common, with a minor allele frequency as high as 3% (Gene Reviews), suggesting that an allele frequency of 3% for this missense variant, as observed in the African gnomAD subpopulation, should not automatically rule out pathogenicity. c.200G>A has been reported in the literature in individuals affected with chronic or acute recurrent pancreatitis (Werlin 2014, Boulling 2012, Giefer 2017, Jalaly 2017, Muller_2019, Scheers_2019). These reports however, do not provide unequivocal conclusions about association of the variant with the disease. At least two publications reported experimental evidence evaluating the variant impact, and demonstrated no splice change or mRNA expression level alteration (Wu 2017), but loss of PST1 protein (encoded by SPINK1) via Western blotting; however, authors used a monoclonal antibody in these expression studies which might be subject to loss of binding with certain amino acid alterations, so the reduction in PST1 levels based on this experiment alone could not be accurately assessed (Boulling 2012). Five ClinVar submitters (evaluation after 2014) cite the variant as benign (n=3) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign, until additional information becomes available. -

SPINK1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 04, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.041
Sift	Benign	0.27	T
Sift4G	Benign	0.14	T
Polyphen		0.36	B
Vest4		0.71
MVP		0.76
MPC		0.023
ClinPred		0.0092	T
GERP RS		3.3
Varity_R		0.16
gMVP		0.54

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: rs35523678; hg19: chr5-147204264;