rs121908403

chr19-38290215-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 12P and 5B. PM1 PP3_Moderate PP5_Very_Strong BS1_Supporting BS2

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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.39

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain BPTI/Kunitz inhibitor 2 (size 50) in uniprot entity SPIT2_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_021102.4
• 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 GnomAd at 21 AD gene.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152208 Hom.: 0 Cov.: 33

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: 52 AN: 251384 Hom.: 0 AF XY: 0.000191 AC XY: 26 AN XY: 135884

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.: 0 Cov.: 31 AF XY: 0.000191 AC XY: 139 AN XY: 726394

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: 21 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74350

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.: 0

Bravo AF: 0.000121

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000305 AC: 37

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital secretory sodium diarrhea 3 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2014	- -
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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

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	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T;.;.
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	4.3	H;.;.;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Uncertain	0.65	T
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	D
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

Other links and lift over

dbSNP: rs121908403; hg19: chr19-38780855;