chr12-109798820-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP2PP5_Moderate

The NM_021625.5(TRPV4):​c.946C>A​(p.Arg316Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R316H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

TRPV4
NM_021625.5 missense

Scores

3
4
12

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.03
Variant links:
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 Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr12-109798819-C-T is described in Lovd as [Pathogenic].
PP2
Missense variant in the TRPV4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 63 curated pathogenic missense variants (we use a threshold of 10). The gene has 35 curated benign missense variants. Gene score misZ: 1.9225 (below the threshold of 3.09). Trascript score misZ: 3.5609 (above the threshold of 3.09). GenCC associations: The gene is linked to TRPV4-related bone disorder, metatropic dysplasia, Charcot-Marie-Tooth disease axonal type 2C, spondylometaphyseal dysplasia, Kozlowski type, familial avascular necrosis of femoral head, parastremmatic dwarfism, neuromuscular disease, autosomal dominant brachyolmia, familial digital arthropathy-brachydactyly, neuronopathy, distal hereditary motor, autosomal dominant 8, scapuloperoneal spinal muscular atrophy, autosomal dominant.
PP5
Variant 12-109798820-G-T is Pathogenic according to our data. Variant chr12-109798820-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 424307.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TRPV4NM_021625.5 linkc.946C>A p.Arg316Ser missense_variant Exon 6 of 16 ENST00000261740.7 NP_067638.3 Q9HBA0-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TRPV4ENST00000261740.7 linkc.946C>A p.Arg316Ser missense_variant Exon 6 of 16 1 NM_021625.5 ENSP00000261740.2 Q9HBA0-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Mar 20, 2017
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

A variant that is likely pathogenic has been identified in the TRPV4 gene. The R316S variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R316S variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R316S 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 across species. Additionally, different missense variants at the same position (R316C and R316H) and a nearby residue (R315W) have been reported in Human Gene Mutation Database in association with TRPV-related disorders (Deng et al., 2010; Klein et al., 2011), supporting the functional importance of this region of the protein. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.85
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.16
CADD
Uncertain
24
DANN
Benign
0.96
DEOGEN2
Benign
0.27
T;T;.;.;.;.
Eigen
Benign
0.010
Eigen_PC
Benign
0.061
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.79
.;T;T;T;T;T
M_CAP
Benign
0.075
D
MetaRNN
Uncertain
0.64
D;D;D;D;D;D
MetaSVM
Benign
-0.42
T
MutationAssessor
Benign
0.42
N;N;.;N;.;.
PrimateAI
Uncertain
0.76
T
PROVEAN
Benign
-0.48
N;N;N;N;N;N
REVEL
Uncertain
0.37
Sift
Benign
0.62
T;T;T;T;T;T
Sift4G
Benign
0.61
T;T;T;T;T;T
Polyphen
0.99
D;D;D;D;B;P
Vest4
0.76
MutPred
0.57
Gain of ubiquitination at K311 (P = 0.0338);Gain of ubiquitination at K311 (P = 0.0338);.;Gain of ubiquitination at K311 (P = 0.0338);.;.;
MVP
0.77
MPC
1.1
ClinPred
0.74
D
GERP RS
3.5
Varity_R
0.38
gMVP
0.80

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs267607145; hg19: chr12-110236625; API