rs572836774
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong
The NM_003673.4(TCAP):c.226C>T(p.Arg76Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000491 in 1,607,978 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R76H) has been classified as Uncertain significance.
Frequency
Consequence
NM_003673.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TCAP | NM_003673.4 | c.226C>T | p.Arg76Cys | missense_variant | 2/2 | ENST00000309889.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TCAP | ENST00000309889.3 | c.226C>T | p.Arg76Cys | missense_variant | 2/2 | 1 | NM_003673.4 | P1 | |
TCAP | ENST00000578283.1 | c.175-21C>T | intron_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000542 AC: 13AN: 239682Hom.: 0 AF XY: 0.0000460 AC XY: 6AN XY: 130576
GnomAD4 exome AF: 0.0000488 AC: 71AN: 1455798Hom.: 0 Cov.: 30 AF XY: 0.0000442 AC XY: 32AN XY: 723666
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74344
ClinVar
Submissions by phenotype
not provided Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 31, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 19, 2018 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2019 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 11, 2022 | The p.R76C variant (also known as c.226C>T), located in coding exon 2 of the TCAP gene, results from a C to T substitution at nucleotide position 226. The arginine at codon 76 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was reported in one individual with intestinal pseudo-obstruction, and functional studies suggested some impact on sodium channel kinetics; however, cardiac details were not provided, and the clinical impact of experimental findings has not been determined (Mazzone A et al. J. Biol. Chem., 2008 Jun;283:16537-44; Poh YC et al. J. Theor. Biol., 2012 Jan;293:41-8). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Primary familial hypertrophic cardiomyopathy;C4225408:Hypertrophic cardiomyopathy 25 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 24, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 76 of the TCAP protein (p.Arg76Cys). This variant is present in population databases (rs572836774, gnomAD 0.01%). This missense change has been observed in individual(s) with intestinal pseudo-obstruction (PMID: 18408010). ClinVar contains an entry for this variant (Variation ID: 202112). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TCAP function (PMID: 18408010, 21959314). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at