chr12-109794021-G-A
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2
The ENST00000261740.7(TRPV4):c.1493C>T(p.Pro498Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000262 in 1,601,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P498P) has been classified as Likely benign.
Frequency
Consequence
ENST00000261740.7 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TRPV4 | NM_021625.5 | c.1493C>T | p.Pro498Leu | missense_variant, splice_region_variant | 9/16 | ENST00000261740.7 | NP_067638.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TRPV4 | ENST00000261740.7 | c.1493C>T | p.Pro498Leu | missense_variant, splice_region_variant | 9/16 | 1 | NM_021625.5 | ENSP00000261740 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151988Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000575 AC: 13AN: 226094Hom.: 0 AF XY: 0.0000491 AC XY: 6AN XY: 122180
GnomAD4 exome AF: 0.0000276 AC: 40AN: 1449780Hom.: 0 Cov.: 34 AF XY: 0.0000264 AC XY: 19AN XY: 719886
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151988Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74236
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease axonal type 2C Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 14, 2021 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with TRPV4-related conditions. ClinVar contains an entry for this variant (Variation ID: 409286). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 498 of the TRPV4 protein (p.Pro498Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at