chr12-109792775-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1BS2
The NM_021625.5(TRPV4):c.1701C>A(p.Tyr567*) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000173 in 1,613,966 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_021625.5 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152202Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251126Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135766
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461764Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7AN XY: 727176
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152202Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74346
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease Uncertain:2
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Inborn genetic diseases Uncertain:1
The p.Y567* variant (also known as c.1701C>A), located in coding exon 10 of the TRPV4 gene, results from a C to A substitution at nucleotide position 1701. This changes the amino acid from a tyrosine to a stop codon within coding exon 10. This alteration was reported to co-occur with the MFN2 p.M376V variant in an individual with Charcot-Marie-Tooth disease type 2 (CMT2) and his affected father, with MFN2 p.M376V considered to be causative of disease; additionally, western blotting demonstrated that protein expression of TRPV4 in this individual's lymphoblasts was comparable with control lymphoblasts (Fawcett KA et al. J Neurol Neurosurg Psychiatry, 2012 Dec;83:1204-9). This alteration is expected to result in premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of TRPV4 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Charcot-Marie-Tooth disease axonal type 2C Uncertain:1
This sequence change creates a premature translational stop signal (p.Tyr567*) in the TRPV4 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TRPV4 cause disease. This variant is present in population databases (rs515726156, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with clinical features of TRPV4-related conditions (PMID: 22851605, 32376792). ClinVar contains an entry for this variant (Variation ID: 126466). Studies have shown that this premature translational stop signal does not significantly alter or has an unclear effect on TRPV4 gene expression (PMID: 22851605). 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. -
not provided Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at