chr12-109803048-G-A
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_021625.5(TRPV4):c.655C>T(p.Arg219Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R219H) has been classified as Uncertain significance.
Frequency
Consequence
NM_021625.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRPV4 | NM_021625.5 | c.655C>T | p.Arg219Cys | missense_variant | 4/16 | ENST00000261740.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRPV4 | ENST00000261740.7 | c.655C>T | p.Arg219Cys | missense_variant | 4/16 | 1 | NM_021625.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152224Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251176Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135802
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461800Hom.: 0 Cov.: 34 AF XY: 0.00000963 AC XY: 7AN XY: 727192
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152224Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74366
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 29, 2017 | - - |
Charcot-Marie-Tooth disease axonal type 2C Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 21, 2023 | 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. 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 not expected to disrupt TRPV4 protein function. ClinVar contains an entry for this variant (Variation ID: 448712). This variant has not been reported in the literature in individuals affected with TRPV4-related conditions. This variant is present in population databases (rs754023659, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 219 of the TRPV4 protein (p.Arg219Cys). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at