rs373103155

Positions:

chr12-109794478-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2PP3BS2

The NM_021625.5(TRPV4):c.1342G>A(p.Glu448Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

TRPV4
NM_021625.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.77

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 -2 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). The gene has 63 curated pathogenic missense variants (we use a threshold of 10). The gene has 35 curated benign missense variants. GenCC has associacion of the 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, 0.767

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPV4	NM_021625.5 link	c.1342G>A	p.Glu448Lys	missense_variant	8/16	ENST00000261740.7	NP_067638.3	Q9HBA0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPV4	ENST00000261740.7 link	c.1342G>A	p.Glu448Lys	missense_variant	8/16	1	NM_021625.5	ENSP00000261740.2		Q9HBA0-1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251202

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461662

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152026

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74238

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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

Jan 24, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 448 of the TRPV4 protein (p.Glu448Lys). This variant is present in population databases (rs373103155, gnomAD 0.003%). 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: 536869). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.75

D;D;.;.;.;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.86

.;D;D;T;D;D

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.77

D;D;D;D;D;D

MetaSVM

Uncertain

0.54

MutationAssessor

Benign

1.4

L;L;.;.;.;.

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-2.8

D;D;N;N;D;D

REVEL

Pathogenic

0.70

Sift

Benign

0.058

T;T;D;T;T;T

Sift4G

Benign

0.13

T;T;T;T;T;T

Polyphen

1.0

D;D;D;D;P;P

Vest4

0.86

MVP

0.98

MPC

1.3

ClinPred

0.96

GERP RS

4.6

Varity_R

0.36

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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