12-109792689-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate

The NM_021625.5(TRPV4):​c.1787T>C​(p.Leu596Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: not found (cov: 31)

Consequence

TRPV4
NM_021625.5 missense

Scores

12
6
1

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 9.32
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.

PM1
In a topological_domain Cytoplasmic (size 14) in uniprot entity TRPV4_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_021625.5
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TRPV4. . Gene score misZ 1.9225 (greater than the threshold 3.09). Trascript score misZ 3.5609 (greater than threshold 3.09). GenCC has associacion of gene with 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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.914

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TRPV4NM_021625.5 linkuse as main transcriptc.1787T>C p.Leu596Pro missense_variant 11/16 ENST00000261740.7 NP_067638.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TRPV4ENST00000261740.7 linkuse as main transcriptc.1787T>C p.Leu596Pro missense_variant 11/161 NM_021625.5 ENSP00000261740 P1Q9HBA0-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
31

ClinVar

Significance: not provided
Submissions summary: Other:1
Revision: no classification provided
LINK: link

Submissions by phenotype

Skeletal dysplasia Other:1
not provided, no classification providedliterature onlyGeneReviews-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.98
D;D;.;.;.;.
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.90
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.91
.;D;D;D;D;D
M_CAP
Pathogenic
0.38
D
MetaRNN
Pathogenic
0.91
D;D;D;D;D;D
MetaSVM
Uncertain
0.65
D
MutationAssessor
Uncertain
2.6
M;M;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Uncertain
-4.1
D;D;D;D;D;D
REVEL
Pathogenic
0.91
Sift
Uncertain
0.0030
D;D;D;D;D;D
Sift4G
Uncertain
0.020
D;D;D;D;D;D
Polyphen
1.0
D;D;D;D;D;D
Vest4
0.96
MutPred
0.70
Gain of catalytic residue at R594 (P = 2e-04);Gain of catalytic residue at R594 (P = 2e-04);.;.;.;.;
MVP
0.99
MPC
2.5
ClinPred
0.99
D
GERP RS
6.1
Varity_R
0.73
gMVP
0.97

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: rs515726159; hg19: chr12-110230494; API