chr19-38264895-G-A
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate
The NM_021102.4(SPINT2):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,382,268 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: not found (cov: 32)
Exomes 𝑓: 0.0000022 ( 0 hom. )
Consequence
SPINT2
NM_021102.4 start_lost
NM_021102.4 start_lost
Scores
5
5
6
Clinical Significance
Conservation
PhyloP100: 1.24
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_021102.4 (SPINT2) was described as [Pathogenic] in ClinVar as 5208
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-38264895-G-A is Pathogenic according to our data. Variant chr19-38264895-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1394791.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPINT2 | NM_021102.4 | c.3G>A | p.Met1? | start_lost | 1/7 | ENST00000301244.12 | |
SPINT2 | NM_001166103.2 | c.3G>A | p.Met1? | start_lost | 1/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPINT2 | ENST00000301244.12 | c.3G>A | p.Met1? | start_lost | 1/7 | 1 | NM_021102.4 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000217 AC: 3AN: 1382268Hom.: 0 Cov.: 31 AF XY: 0.00000293 AC XY: 2AN XY: 682110
GnomAD4 exome
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3
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1382268
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31
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2
AN XY:
682110
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 24, 2022 | For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of the initiator codon alters SPINT2 gene expression (PMID: 19185281). ClinVar contains an entry for this variant (Variation ID: 1394791). Disruption of the initiator codon has been observed in individual(s) with congenital tufting enteropathy and/or syndromic congenital sodium diarrhea (PMID: 19185281, 24142340). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the SPINT2 mRNA. The next in-frame methionine is located at codon 51. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
PROVEAN
Benign
N;N;.
REVEL
Uncertain
Sift
Pathogenic
D;D;.
Sift4G
Pathogenic
D;D;D
Polyphen
B;.;.
Vest4
MutPred
Gain of catalytic residue at M1 (P = 0.0455);Gain of catalytic residue at M1 (P = 0.0455);Gain of catalytic residue at M1 (P = 0.0455);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at