Variant rs515726168 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BS2

The NM_021625.5(TRPV4):c.652G>A(p.Glu218Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,826 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

TRPV4
NM_021625.5 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1O:1

Conservation

PhyloP100: 2.08

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

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.

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPV4	NM_021625.5 linkuse as main transcript	c.652G>A	p.Glu218Lys	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.652G>A	p.Glu218Lys	missense_variant	4/16	1	NM_021625.5	ENSP00000261740	P1	Q9HBA0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461826

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

- -

not provided

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.35

T;T;.;.;.;.

Eigen

Benign

0.16

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.87

.;D;D;T;D;D

M_CAP

Benign

0.078

MetaRNN

Uncertain

0.46

T;T;T;T;T;T

MetaSVM

Uncertain

0.28

MutationAssessor

Benign

2.0

M;M;M;M;M;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.8

N;N;N;N;N;N

REVEL

Pathogenic

0.69

Sift

Benign

0.14

T;T;T;T;T;T

Sift4G

Benign

0.23

T;T;T;T;T;T

Polyphen

0.99

D;D;D;D;B;B

Vest4

0.41

MutPred

0.60

Gain of ubiquitination at E218 (P = 0.0351);Gain of ubiquitination at E218 (P = 0.0351);Gain of ubiquitination at E218 (P = 0.0351);Gain of ubiquitination at E218 (P = 0.0351);Gain of ubiquitination at E218 (P = 0.0351);.;

MVP

0.94

MPC

0.61

ClinPred

0.86

GERP RS

4.5

Varity_R

0.21

gMVP

0.79

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