rs143014431

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. K66K) has been classified as Likely benign.

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:7

Conservation

PhyloP100: -0.0960

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

hereditary chronic pancreatitis
Inheritance: AD, Unknown Classification: STRONG, SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia
tropical pancreatitis
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia

SPINK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

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

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000335 (51/152146) while in subpopulation NFE AF = 0.000661 (45/68030). AF 95% confidence interval is 0.000508. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 51 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINK1	NM_001379610.1 link	c.198A>C	p.Lys66Asn	missense_variant	Exon 4 of 4	ENST00000296695.10	NP_001366539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINK1	ENST00000296695.10 link	c.198A>C	p.Lys66Asn	missense_variant	Exon 4 of 4	1	NM_001379610.1	ENSP00000296695.5		P00995
SPINK1	ENST00000505722.1 link	n.113A>C		non_coding_transcript_exon_variant	Exon 2 of 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

GnomAD2 exomes

AF:

0.000200

AC:

AN:

250312

AF XY:

0.000185

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 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

African (AFR)

AF:

0.000239

AC:

AN:

33476

American (AMR)

AF:

0.000179

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000508

AC:

565

AN:

1111942

Other (OTH)

AF:

0.000811

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

125

156

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000335

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74330

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41438

American (AMR)

AF:

0.0000655

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000661

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000296

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:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary pancreatitis;C1842402:Tropical pancreatitis

Uncertain:2

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

May 15, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary pancreatitis

Uncertain:2

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

May 22, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Feb 11, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. This frequency is not significantly higher than estimated for a pathogenic variant in SPINK1 causing Chronic Pancreatitis (0.0002 vs 0.022), allowing no conclusion about variant significance. 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 do not allow any conclusion about variant significance. Publications report experimental evidence evaluating an impact on protein function. 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). 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). The following publications have been ascertained in the context of this evaluation (PMID: 17003641, 22526274, 22343981, 21952138, 22749696, 28502372, 28994706, 33515547, 35974416). ClinVar contains an entry for this variant (Variation ID: 410699). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Oct 29, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SPINK1-related disorder

Uncertain:1

Jan 29, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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

PhyloP100

-0.096

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

Mutation Taster

=27/73

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs143014431

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over