rs200497189

Positions:

chr12-109803087-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4BP6BS2

The ENST00000261740.7(TRPV4):c.616C>T(p.Arg206Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000427 in 1,614,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R206H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

TRPV4
ENST00000261740.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.00

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]

TRPV4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.2845802).

BP6

Variant 12-109803087-G-A is Benign according to our data. Variant chr12-109803087-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 520860.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAdExome4 at 65 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPV4	NM_021625.5 linkuse as main transcript	c.616C>T	p.Arg206Cys	missense_variant	4/16	ENST00000261740.7	NP_067638.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPV4	ENST00000261740.7 linkuse as main transcript	c.616C>T	p.Arg206Cys	missense_variant	4/16	1	NM_021625.5	ENSP00000261740	P1	Q9HBA0-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

251228

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000445

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000396

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000625

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2C

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 17, 2023

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TRPV4 protein function. 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: 520860). This variant has not been reported in the literature in individuals affected with TRPV4-related conditions. This variant is present in population databases (rs200497189, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 206 of the TRPV4 protein (p.Arg206Cys). -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2019

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

D;D;.;.;.;.

Eigen

Benign

0.13

Eigen_PC

Benign

0.080

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.74

.;T;D;T;D;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.28

T;T;T;T;T;T

MetaSVM

Uncertain

0.51

MutationAssessor

Benign

1.8

L;L;L;L;L;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;N

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-3.6

D;D;D;D;D;D

REVEL

Uncertain

0.54

Sift

Uncertain

0.011

D;D;D;D;D;D

Sift4G

Uncertain

0.037

D;D;D;T;D;D

Polyphen

1.0

D;D;D;D;D;D

Vest4

0.29

MVP

0.95

MPC

0.53

ClinPred

0.24

GERP RS

4.5

Varity_R

0.22

gMVP

0.61

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over