rs121908403

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 10P and 1B. PP3_ModeratePP5_Very_StrongBS1_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

Publications

20 publications found

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 Gene-Disease associations (from GenCC):

syndromic congenital sodium diarrhea
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
congenital secretory sodium diarrhea 3
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)

SPINT2 links:

ENSG00000267748 (HGNC:):

ENSG00000267748 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 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 VariationId is 5205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 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 GnomAdExome4. There are 139 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPINT2	NM_021102.4 link	c.488A>G	p.Tyr163Cys	missense_variant	Exon 5 of 7	ENST00000301244.12	NP_066925.1	O43291-1
SPINT2	NM_001166103.2 link	c.317A>G	p.Tyr106Cys	missense_variant	Exon 4 of 6		NP_001159575.1	O43291-2A0A140VJV6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPINT2	ENST00000301244.12 link	c.488A>G	p.Tyr163Cys	missense_variant	Exon 5 of 7	1	NM_021102.4	ENSP00000301244.5		O43291-1
ENSG00000267748	ENST00000591889.2 link	c.119A>G	p.Tyr40Cys	missense_variant	Exon 2 of 6	2		ENSP00000468040.1		K7EQZ3

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

GnomAD2 exomes

AF:

0.000207

AC:

AN:

251384

AF XY:

0.000191

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 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

African (AFR)

AF:

0.0000598

AC:

AN:

33426

American (AMR)

AF:

0.0000447

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86178

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4360

European-Non Finnish (NFE)

AF:

0.000254

AC:

282

AN:

1112002

Other (OTH)

AF:

0.000133

AC:

AN:

60234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000138

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68036

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000280

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

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Mar 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Nov 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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

(source)

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;.;.;.

PhyloP100

4.4

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

PromoterAI

-0.0085

Neutral

(source)

Varity_R

0.89

gMVP

0.99

Mutation Taster

=4/96

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

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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