5-147824702-G-A

Position:

chr5-147824702-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001379610.1(SPINK1):c.199C>T(p.Arg67Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,762 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R67H) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

SPINK1
NM_001379610.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6O:1

Conservation

PhyloP100: 1.13

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 -4 ACMG points.

BS2

High AC in GnomAdExome4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINK1	NM_001379610.1 linkuse as main transcript	c.199C>T	p.Arg67Cys	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.199C>T	p.Arg67Cys	missense_variant	4/4	1	NM_001379610.1	ENSP00000296695.5		P00995
SPINK1	ENST00000505722.1 linkuse as main transcript	n.114C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000320

AC:

AN:

250282

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135334

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000996

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1461668

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000301

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary pancreatitis

Uncertain:3Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 07, 2023	The p.R67C variant (also known as c.199C>T), located in coding exon 4 of the SPINK1 gene, results from a C to T substitution at nucleotide position 199. The arginine at codon 67 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been identified in multiple individuals diagnosed with pancreatitis (Kuwata K et al. J Gastroenterol, 2001 Sep;36:612-8; Zou WB et al. Clin Transl Gastroenterol, 2018 Nov;9:204). In vitro expression analysis revealed that the p.R67C allele results in intracellular retention and significantly decreased secretion of the SPINK1 gene product compared to wild type (Király O et al. Gut, 2007 Oct;56:1433-8). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 24, 2022	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 67 of the SPINK1 protein (p.Arg67Cys). 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. Experimental studies have shown that this missense change affects SPINK1 function (PMID: 17525091, 17568390). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 132145). This missense change has been observed in individual(s) with chronic pancreatitis (PMID: 11578065, 22427236, 30420730, 33515547). This variant is present in population databases (rs515726208, gnomAD 0.01%). -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 12, 2024

Variant summary: SPINK1 c.199C>T (p.Arg67Cys) results in a non-conservative amino acid change located in the Kazal domain (IPR001239) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 250282 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. 199C>T has been reported in the literature in individuals affected with Chronic Pancreatitis (example:Kuwata_2001, Zou_2018, Szabo_2021 and Rosendahl_2012). Multiple publications have reported experimental evidence evaluating an impact on protein function (example: Boulling_2007, Kiraly_2007, Wu_2017). However these reports do not provide unequivocal conclusions about association of the variant with Chronic Pancreatitis Risk. The following publications have been ascertained in the context of this evaluation (PMID: 17568390, 17525091, 11578065, 22427236, 33515547, 28994706, 30420730). ClinVar contains an entry for this variant (Variation ID: 132145). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary pancreatitis;C1842402:Tropical pancreatitis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 25, 2024

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Mar 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

Eigen

Benign

-0.022

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.56

M_CAP

Benign

0.081

MetaRNN

Uncertain

0.62

MetaSVM

Benign

-0.55

PrimateAI

Benign

0.37

PROVEAN

Pathogenic

-4.6

REVEL

Benign

0.28

Sift

Benign

0.074

Sift4G

Uncertain

0.056

Polyphen

1.0

Vest4

0.54

MutPred

0.36

Gain of methylation at K66 (P = 0.0229);

MVP

0.82

MPC

0.15

ClinPred

0.57

GERP RS

3.1

Varity_R

0.30

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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