rs515726156
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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.Tyr567Ter) 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
Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
TRPV4
NM_021625.5 stop_gained
NM_021625.5 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 5.04
Genes affected
TRPV4 (HGNC:18083): (transient receptor potential cation channel subfamily V member 4) This gene encodes a member of the OSM9-like transient receptor potential channel (OTRPC) subfamily in the transient receptor potential (TRP) superfamily of ion channels. The encoded protein is a Ca2+-permeable, nonselective cation channel that is thought to be involved in the regulation of systemic osmotic pressure. Mutations in this gene are the cause of spondylometaphyseal and metatropic dysplasia and hereditary motor and sensory neuropathy type IIC. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2010]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
BS2
?
High AC in GnomAdExome4 at 26 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRPV4 | NM_021625.5 | c.1701C>A | p.Tyr567Ter | stop_gained | 11/16 | ENST00000261740.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRPV4 | ENST00000261740.7 | c.1701C>A | p.Tyr567Ter | stop_gained | 11/16 | 1 | NM_021625.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152202Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251126Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135766
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GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461764Hom.: 0 Cov.: 33 AF XY: 0.00000963 AC XY: 7AN XY: 727176
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152202Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74346
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Charcot-Marie-Tooth disease Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Genetics Laboratory, London Health Sciences Centre | - | - - |
Uncertain significance, no assertion criteria provided | literature only | Inherited Neuropathy Consortium | - | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 19, 2021 | 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
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 05, 2023 | 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. ClinVar contains an entry for this variant (Variation ID: 126466). This premature translational stop signal has been observed in individual(s) with clinical features of TRPV4-related conditions (PMID: 22851605, 32376792). This variant is present in population databases (rs515726156, gnomAD 0.004%). 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. - |
not provided Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A;A;A;A;A;A
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at