12-109814760-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_021625.5(TRPV4):​c.37G>A​(p.Gly13Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000032 in 1,563,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G13W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

TRPV4
NM_021625.5 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.787
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_benign. Variant got -5 ACMG points.

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.
BP4
Computational evidence support a benign effect (MetaRNN=0.17686468).
BS2
High AC in GnomAdExome4 at 48 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TRPV4NM_021625.5 linkc.37G>A p.Gly13Arg missense_variant Exon 2 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.37G>A p.Gly13Arg missense_variant Exon 2 of 16 1 NM_021625.5 ENSP00000261740.2 Q9HBA0-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152122
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000368
AC:
6
AN:
163186
Hom.:
0
AF XY:
0.0000338
AC XY:
3
AN XY:
88802
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000766
Gnomad ASJ exome
AF:
0.000116
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000843
Gnomad NFE exome
AF:
0.0000150
Gnomad OTH exome
AF:
0.000218
GnomAD4 exome
AF:
0.0000340
AC:
48
AN:
1411408
Hom.:
0
Cov.:
32
AF XY:
0.0000258
AC XY:
18
AN XY:
698322
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000533
Gnomad4 ASJ exome
AF:
0.0000394
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000493
Gnomad4 FIN exome
AF:
0.0000220
Gnomad4 NFE exome
AF:
0.0000340
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152122
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74306
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000868
Hom.:
0
Bravo
AF:
0.0000302
ExAC
AF:
0.0000173
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Distal spinal muscular atrophy Uncertain:1
Aug 14, 2019
Genesis Genome Database
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

- -

Charcot-Marie-Tooth disease axonal type 2C Uncertain:1
Oct 22, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 13 of the TRPV4 protein (p.Gly13Arg). This variant is present in population databases (rs763302555, gnomAD 0.01%). 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: 246224). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TRPV4 protein function with a negative predictive value of 95%. 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 Uncertain:1
Dec 12, 2017
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The G13R variant in the TRPV4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. No data from the NHLBI Exome Sequencing Project population cohort was available to assess the frequency of this variant. The G13R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant likely does not alter the protein structure/function. We interpret G13R as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.096
BayesDel_addAF
Benign
-0.068
T
BayesDel_noAF
Benign
-0.15
CADD
Benign
18
DANN
Uncertain
0.99
DEOGEN2
Benign
0.29
T;T;.;.;.;.
Eigen
Benign
-0.55
Eigen_PC
Benign
-0.60
FATHMM_MKL
Benign
0.052
N
LIST_S2
Benign
0.74
.;T;T;T;T;T
M_CAP
Uncertain
0.21
D
MetaRNN
Benign
0.18
T;T;T;T;T;T
MetaSVM
Uncertain
-0.16
T
MutationAssessor
Benign
0.20
N;N;N;N;N;N
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-0.58
N;N;N;N;N;N
REVEL
Benign
0.26
Sift
Benign
0.088
T;T;D;D;T;D
Sift4G
Benign
0.24
T;T;D;T;T;T
Polyphen
0.94
P;P;P;D;D;D
Vest4
0.074
MutPred
0.16
Gain of catalytic residue at P8 (P = 0.2232);Gain of catalytic residue at P8 (P = 0.2232);Gain of catalytic residue at P8 (P = 0.2232);Gain of catalytic residue at P8 (P = 0.2232);Gain of catalytic residue at P8 (P = 0.2232);Gain of catalytic residue at P8 (P = 0.2232);
MVP
0.89
MPC
0.47
ClinPred
0.091
T
GERP RS
2.6
Varity_R
0.038
gMVP
0.14

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: rs763302555; hg19: chr12-110252565; API