rs760044422
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4BS2
The NM_021625.5(TRPV4):āc.1912C>Gā(p.Pro638Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000613 in 1,614,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P638L) has been classified as Likely benign.
Frequency
Consequence
NM_021625.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRPV4 | NM_021625.5 | c.1912C>G | p.Pro638Ala | missense_variant | 13/16 | ENST00000261740.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRPV4 | ENST00000261740.7 | c.1912C>G | p.Pro638Ala | missense_variant | 13/16 | 1 | NM_021625.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152228Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000439 AC: 11AN: 250480Hom.: 0 AF XY: 0.0000591 AC XY: 8AN XY: 135470
GnomAD4 exome AF: 0.0000650 AC: 95AN: 1461826Hom.: 0 Cov.: 33 AF XY: 0.0000591 AC XY: 43AN XY: 727208
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152228Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74380
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 31, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 23, 2015 | The P638A variant in the TRPV4 gene has been reported previously in a study looking for TRPV4 variants in individuals with inherited neuropathies and control individuals; P638A was detected in a control individual (Fawcett et al., 2012). The P638A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P638A variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret P638A as a variant of uncertain significance, - |
Charcot-Marie-Tooth disease Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
Charcot-Marie-Tooth disease axonal type 2C Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 30, 2023 | This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 638 of the TRPV4 protein (p.Pro638Ala). This variant is present in population databases (rs760044422, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with TRPV4-related conditions. ClinVar contains an entry for this variant (Variation ID: 234727). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TRPV4 protein function. 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. - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 08, 2020 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at