5-147828022-C-T

Position:

chr5-147828022-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001379610.1(SPINK1):c.194G>A(p.Arg65Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000719 in 1,609,898 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00061 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 1 hom. )

Consequence

SPINK1
NM_001379610.1 missense, splice_region

Scores

Splicing: ADA: 0.8899

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:2U:7

Conservation

PhyloP100: -1.44

Variant links:

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]

SPINK1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024398416).

BS2

High AC in GnomAd4 at 92 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINK1	NM_001379610.1 linkuse as main transcript	c.194G>A	p.Arg65Gln	missense_variant, splice_region_variant	3/4	ENST00000296695.10	NP_001366539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
SPINK1	ENST00000296695.10 linkuse as main transcript	c.194G>A	p.Arg65Gln	missense_variant, splice_region_variant	3/4	1	NM_001379610.1	ENSP00000296695	P1
SPINK1	ENST00000510027.2 linkuse as main transcript	c.194G>A	p.Arg65Gln	missense_variant	3/3	3		ENSP00000427376
SPINK1	ENST00000505722.1 linkuse as main transcript	n.109G>A		splice_region_variant, non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.000606

AC:

AN:

151888

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000418

Gnomad FIN

AF:

0.000473

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00102

Gnomad OTH

AF:

0.000960

GnomAD3 exomes

AF:

0.000546

AC:

136

AN:

248944

Hom.:

AF XY:

0.000528

AC XY:

AN XY:

134586

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000297

Gnomad FIN exome

AF:

0.000330

Gnomad NFE exome

AF:

0.000951

Gnomad OTH exome

AF:

0.000493

GnomAD4 exome

AF:

0.000731

AC:

1066

AN:

1457892

Hom.:

Cov.:

AF XY:

0.000684

AC XY:

496

AN XY:

725390

show subpopulations

Gnomad4 AFR exome

AF:

0.0000899

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000268

Gnomad4 FIN exome

AF:

0.000435

Gnomad4 NFE exome

AF:

0.000881

Gnomad4 OTH exome

AF:

0.000465

GnomAD4 genome

AF:

0.000605

AC:

AN:

152006

Hom.:

Cov.:

AF XY:

0.000592

AC XY:

AN XY:

74310

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000418

Gnomad4 FIN

AF:

0.000473

Gnomad4 NFE

AF:

0.00102

Gnomad4 OTH

AF:

0.000950

Alfa

AF:

0.0654

Hom.:

2348

Bravo

AF:

0.000570

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000412

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 29, 2023	The SPINK1 c.194G>A; p.Arg65Gln variant (rs141634296) is reported in the literature in individuals diagnosed with chronic pancreatitis (Keiles 2006, Ockenga 2001, Rosendahl 2013, Szabo 2021, Zou 2018). This variant is also reported in ClinVar (Variation ID: 36779). It is observed in the general population with an overall allele frequency of 0.05% (154/280326 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.448). Functional characterization of the variant indicates a reduced production and secretion of the SPINK1 mRNA and protein, resulting in reduced overall enzymatic activity (Boulling 2012, Beer 2014, Kiraly 2007). However, the variant has also been described as a reduced penetrance allele based on familial segregation (Ockenga 2001). Due to the conflicting information, the clinical significance of the p.Arg65Gln variant is uncertain at this time. References: Beer S et al. Exonic variants affecting pre-mRNA splicing add to genetic burden in chronic pancreatitis. Gut. 2014 May;63(5):860-1. PMID: 24052272. Boulling A et al. Functional analysis of eight missense mutations in the SPINK1 gene. Pancreas. 2012 Mar;41(2):329-30. PMID: 22343981. Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. PMID: 17003641. Kiraly O et al. Missense mutations in pancreatic secretory trypsin inhibitor (SPINK1) cause intracellular retention and degradation. Gut. 2007 Oct;56(10):1433-8. PMID: 17525091. Ockenga J et al. Low prevalence of SPINK1 gene mutations in adult patients with chronic idiopathic pancreatitis. J Med Genet. 2001 Apr;38(4):243-4. PMID: 11368029. Rosendahl J et al. CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated? Gut. 2013 Apr;62(4):582-92. PMID: 22427236. Szabo A et al. Defective binding of SPINK1 variants is an uncommon mechanism for impaired trypsin inhibition in chronic pancreatitis. J Biol Chem. 2021 Jan-Jun;296:100343. PMID: 33515547. 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. -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary pancreatitis

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 30, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 65 of the SPINK1 protein (p.Arg65Gln). This variant is present in population databases (rs141634296, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with idiopathic chronic pancreatitis (PMID: 11368029, 17003641, 22427236, 23951356). ClinVar contains an entry for this variant (Variation ID: 36779). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects SPINK1 function (PMID: 17525091, 17568390). Studies have shown that this missense change does not affect mRNA splicing (PMID: 24052272, 28320769). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 29, 2023	The p.R65Q variant (also known as c.194G>A), located in coding exon 3 of the SPINK1 gene, results from a G to A substitution at nucleotide position 194. The arginine at codon 65 is replaced by glutamine, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 3 and may have some effect on normal mRNA splicing. This variant was first described in a 35-year-old male with pancreatitis, who was also heterozygous for a pathogenic CFTR mutation (p.Y1092*); however, both of these alterations were also identified in the patient's asymptomatic sister and mother (Ockenga J et al. J Med Genet. 2001; 38(4):243-4). While mini-gene assays suggested that this mutant would lead to decreased protein expression (Boulling A et al. Eur J Hum Genet. 2007;15:936-942; Beer S, Gut 2014 May; 63(5):860-1), a recent study with full gene reported no effect on either mRNA splicing or expression (Wu H et al. Gut, 2017 Dec;66:2195-2196). In another study, this variant was described to reduce protein secretion but not the activity (Király O et al. Gut. 2007; 56:1433-8). This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. This amino acid position is poorly conserved in available vertebrate species. In addition, as a missense substitution this is predicted to be tolerated by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. -
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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 11, 2023

Variant summary: SPINK1 c.194G>A (p.Arg65Gln) 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. Several computational tools predict a significant impact on normal splicing: Two predict the variant creates a 3' acceptor site. Four predict the variant weakens a 5' donor site. Functional studies have generated conflicting results with regard to mRNA splicing: Beer_2014 showed a ~75% reduction in SPINK1 mRNA and protein expression using a partial SPINK1 gene in the minigene system, whereas Wu_2017 showed no effect on mRNA expression using full-length SPINK1 in a minigene system. However, both studies were performed in HEK293 cells, which may limit the biological relevance of these assays. Additional functional studies showed that protein secretion may be reduced by the variant (Kiraly_2007, Boulling_2007), though the effect of this reduction is unclear (Szabo_2021). The variant allele was found at a frequency of 0.00053 in 254852 control chromosomes (gnomaD). The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in SPINK1 causing Chronic Pancreatitis phenotype (0.00025), strongly suggesting that the variant is benign. c.194G>A has been reported in the literature in individuals affected with Chronic Pancreatitis and Peutz-Jeghers syndrome (Masson_2013 and Bennett_2021). These data indicate that the variant may be associated with disease. However, at least two patients have been reported with the pathogenic mutation SPINK1 p.N34S (Masson 2013, internal sample) in co-occurrence with the variant, supporting a benign outcome. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.22

CADD

Benign

9.3

DANN

Benign

0.79

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.0014

LIST_S2

Benign

0.42

T;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.024

T;T

MetaSVM

Benign

-0.98

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.1

N;N

REVEL

Uncertain

0.45

Sift

Benign

0.33

T;T

Sift4G

Benign

0.39

T;T

Polyphen

0.0

B;.

Vest4

0.12

MVP

0.64

MPC

0.020

ClinPred

0.016

GERP RS

-3.3

Varity_R

0.17

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.89

dbscSNV1_RF

Pathogenic

0.79

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over