rs143014431

Positions:

chr5-147824703-T-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001379610.1(SPINK1):c.198A>C(p.Lys66Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000422 in 1,613,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00043 ( 0 hom. )

Consequence

SPINK1
NM_001379610.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: -0.0960

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:

SPINK1 (HGNC:):

SPINK1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.068697184).

BS2

High AC in GnomAd4 at 51 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINK1	NM_001379610.1 linkuse as main transcript	c.198A>C	p.Lys66Asn	missense_variant	4/4	ENST00000296695.10	NP_001366539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINK1	ENST00000296695.10 linkuse as main transcript	c.198A>C	p.Lys66Asn	missense_variant	4/4	1	NM_001379610.1	ENSP00000296695.5		P00995
SPINK1	ENST00000505722.1 linkuse as main transcript	n.113A>C		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000661

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000200

AC:

AN:

250312

Hom.:

AF XY:

0.000185

AC XY:

AN XY:

135352

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000345

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000431

AC:

630

AN:

1461710

Hom.:

Cov.:

AF XY:

0.000414

AC XY:

301

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000508

Gnomad4 OTH exome

AF:

0.000811

GnomAD4 genome

AF:

0.000335

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000661

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000302

Hom.:

Bravo

AF:

0.000272

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000148

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary pancreatitis

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 16, 2023	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 66 of the SPINK1 protein (p.Lys66Asn). This variant is present in population databases (rs143014431, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with pancreatitis (PMID: 17003641, 28502372, 33515547). ClinVar contains an entry for this variant (Variation ID: 410699). 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 disruptive. Experimental studies have shown that this missense change affects SPINK1 function (PMID: 22343981). 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	May 22, 2024	The p.K66N variant (also known as c.198A>C), located in coding exon 4 of the SPINK1 gene, results from an A to C substitution at nucleotide position 198. The lysine at codon 66 is replaced by asparagine, an amino acid with similar properties. This variant was reported in multiple individuals with chronic or recurrent pancreatitis (Keiles S et al. Pancreas, 2006 Oct;33:221-7; Giefer MJ et al. J Pediatr, 2017 Jul;186:95-100). Functional studies suggest that the variant reduces protein expression; however, additional evidence is needed to confirm this finding (Boulling A et al. Pancreas, 2012 Mar;41:329-30). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jan 11, 2023

Variant summary: SPINK1 c.198A>C (p.Lys66Asn) 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 0.0002 in 250312 control chromosomes, predominantly at a frequency of 0.00035 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in SPINK1 causing Chronic Pancreatitis phenotype (0.00025), suggesting that the variant may be a benign polymorphism found primarily in populations of Non-Finnish European origin. c.198A>C has been reported in the literature in at least two children affected with pancreatitis, one 15-year-old caucasian male referred to genetic testing in whom no other sequence variant in PRSS1, SPINK1 or CFTR genes were identified (Keiles_2006), and in a 1-year-old evaluated as part of the International Study Group of Pediatric Pancreatitis: In Search for a Cure (INSPIRRE) study in whom a co-occurring pathogenic SPINK1 variant (c.101A>G/p.Asn34Ser) was also identified (Giefer_2017). It has also been subsequently cited as a non-primary reference by others (example, Chua_2011, Chen_2012, Kume_2012, Szabo_2021). These data however do not allow any conclusion about variant significance. One study reported a complete loss of expression of the protein product encoding the SPINK1 gene (PTS1) in human embryonic kidney 293T cells transfected with a mutant construct bearing this variant (Boulling_2012). The authors speculate that the possibility of reduced or lack of binding activity of the mutant protein to the monoclonal anti-hPST1 antibody used in their experimental system cannot be ruled out (Boulling_2007). Contradicting this observation, another study reported no difference in splicing or mRNA expression associated with this variant when compared to the wild type, thereby ruling out any impact of this missense variant on pre-mRNA splicing and/or mRNA stability (Wu_2017). Therefore, the functional evidence surrounding this variant is conflicting with authorship overlap between reported studies and later reports (Wu_2017) not citing the previous report (Boulling_2012). Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=2) or pathogenic (n=1), citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, until additional reports of this variant segregating with inherited pancreatitis in multiplex families supported by conclusive functional evidence is identified, the variant retained its classification as a variant of uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Oct 29, 2019

- -

SPINK1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 29, 2024

The SPINK1 c.198A>C variant is predicted to result in the amino acid substitution p.Lys66Asn. This variant has been reported in the heterozygous state in an individual with chronic pancreatitis and to co-occur with another SPINK1 variant (phase unknown) in an individual with early onset acute pancreatitis (Table 3, Keiles et al. 2006. PubMed ID: 17003641; Table III, Giefer et al. 2017. PubMed ID: 28502372). A full-length gene assay to assess pre-mRNA splicing suggests that this variant does not affect pre-mRNA splicing and/or mRNA stability (Table 1, Wu H et al. 2017. PubMed ID: 28994706). However, a study of protein expression in human embryonic kidney 293T (HEK293T) cells showed this variant causes complete loss of SPINK1 protein compared to control (Figure 1, Boulling et al. 2012. PubMed ID: 22343981). This variant is reported in 0.041% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is likely too common to be a primary cause of autosomal dominant disease. Conflicting interpretations of pathogenic and uncertain are present in the ClinVar database for the c.198A>C variant (https://www.ncbi.nlm.nih.gov/clinvar/variation/410699). Although this variant may contribute to chronic pancreatitis phenotypes with reduced penetrance, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.17

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.37

M_CAP

Benign

0.058

MetaRNN

Benign

0.069

MetaSVM

Benign

-0.92

PrimateAI

Benign

0.38

PROVEAN

Benign

-2.3

REVEL

Benign

0.17

Sift

Uncertain

0.021

Sift4G

Benign

0.15

Polyphen

0.30

Vest4

0.095

MutPred

0.80

Loss of ubiquitination at K66 (P = 0.0326);

MVP

0.43

MPC

0.074

ClinPred

0.032

GERP RS

-2.8

Varity_R

0.42

gMVP

0.74

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

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