rs121908403

Positions:

chr19-38290215-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 10P and 2B. PP3_ModeratePP5_Very_StrongBS1_SupportingBS2_Supporting

The NM_021102.4(SPINT2):c.488A>G(p.Tyr163Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000197 in 1,612,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

SPINT2
NM_021102.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 4.39

Variant links:

Genes affected

SPINT2 (HGNC:11247): (serine peptidase inhibitor, Kunitz type 2) This gene encodes a transmembrane protein with two extracellular Kunitz domains that inhibits a variety of serine proteases. The protein inhibits HGF activator which prevents the formation of active hepatocyte growth factor. This gene is a putative tumor suppressor, and mutations in this gene result in congenital sodium diarrhea. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

SPINT2 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.874

PP5

Variant 19-38290215-A-G is Pathogenic according to our data. Variant chr19-38290215-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 5205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-38290215-A-G is described in Lovd as [Pathogenic].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000203 (296/1460170) while in subpopulation NFE AF= 0.000254 (282/1112002). AF 95% confidence interval is 0.000229. There are 0 homozygotes in gnomad4_exome. There are 139 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 21 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPINT2	NM_021102.4 linkuse as main transcript	c.488A>G	p.Tyr163Cys	missense_variant	5/7	ENST00000301244.12	NP_066925.1
SPINT2	NM_001166103.2 linkuse as main transcript	c.317A>G	p.Tyr106Cys	missense_variant	4/6		NP_001159575.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPINT2	ENST00000301244.12 linkuse as main transcript	c.488A>G	p.Tyr163Cys	missense_variant	5/7	1	NM_021102.4	ENSP00000301244	P1	O43291-1
	ENST00000651064.1 linkuse as main transcript	n.533-9T>C		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000279

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000207

AC:

AN:

251384

Hom.:

AF XY:

0.000191

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

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:

0.000431

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000203

AC:

296

AN:

1460170

Hom.:

Cov.:

AF XY:

0.000191

AC XY:

139

AN XY:

726394

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000254

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000138

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.000121

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000305

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital secretory sodium diarrhea 3

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The SPINT2 c.488A>G p.(Tyr163Cys) missense variant has been identified in individuals with a phenotype consistent with (Heinz-Erian et al. 2009; Sivagnanam et al. 2010; Slae et al. 2013; Salomon et al. 2014; d'Apolito et al. 2015). The highest frequency of this allele in the Genome Aggregation Database is 0.0004337 in the European (non-Finnish) population (version 2.1.1). Heinz-Erian et al. (2009) demonstrated a significant decrease in the ability of the p.Tyr163Cys variant protein to inhibit trypsin as compared to wild type when transiently transfected in COS7 cells, and studies in Xenopus oocytes by Faller et al. (2014) showed a complete loss of inhibitory activity by the p.Tyr163Cys variant protein on two proteases, which may ultimately lead to excessive proteolytic activity. Based on the available evidence, the c.488A>G p.(Tyr163Cys) variant is classified as pathogenic for syndromic congenital diarrhea. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2014	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 12, 2023

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 163 of the SPINT2 protein (p.Tyr163Cys). This variant is present in population databases (rs121908403, gnomAD 0.04%). This missense change has been observed in individuals with congenital sodium diarrhea (PMID: 19185281, 30445423). ClinVar contains an entry for this variant (Variation ID: 5205). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SPINT2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SPINT2 function (PMID: 19185281, 30445423). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;T;.;.

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.87

D;D;D;D

MetaSVM

Uncertain

0.29

MutationAssessor

Pathogenic

4.3

H;.;.;.

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-8.7

D;.;D;.

REVEL

Uncertain

0.59

Sift

Pathogenic

0.0

D;.;D;.

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;.;.;.

Vest4

0.93

MVP

0.94

MPC

1.3

ClinPred

1.0

GERP RS

4.5

Varity_R

0.89

gMVP

0.99

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