rs767331924

chr12-109803047-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_021625.5(TRPV4):c.656G>A(p.Arg219His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R219C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TRPV4 NM_021625.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TRPV4
• BP4: Computational evidence support a benign effect (MetaRNN=0.22025335).
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPV4	NM_021625.5	c.656G>A	p.Arg219His	missense_variant	4/16	ENST00000261740.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPV4	ENST00000261740.7	c.656G>A	p.Arg219His	missense_variant	4/16	1	NM_021625.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

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: 2 AN: 251142 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135804

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: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461818 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 727198

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74490

Gnomad4 AFR AF: 0.000120

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

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease axonal type 2C Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 24, 2017

This sequence change replaces arginine with histidine at codon 219 of the TRPV4 protein (p.Arg219His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs767331924, ExAC 0.009%) but has not been reported in the literature in individuals with a TRPV4-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.15
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.41	T;T;.;.;.;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Benign	0.66	D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.22	T;T;T;T;T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.0	L;L;L;L;L;.
MutationTaster	Benign	0.97	D;D;D;D;D;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.0	N;N;N;N;N;N
REVEL	Uncertain	0.44
Sift	Uncertain	0.027	D;D;T;D;D;D
Sift4G	Uncertain	0.055	T;T;D;T;T;T
Polyphen		0.96	D;D;D;D;B;B
Vest4		0.22
MutPred		0.54		Gain of catalytic residue at E218 (P = 0.0012);Gain of catalytic residue at E218 (P = 0.0012);Gain of catalytic residue at E218 (P = 0.0012);Gain of catalytic residue at E218 (P = 0.0012);Gain of catalytic residue at E218 (P = 0.0012);.;
MVP		0.93
MPC		0.49
ClinPred		0.56	D
GERP RS		4.5
Varity_R		0.34
gMVP		0.44

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

Other links and lift over

dbSNP: rs767331924; hg19: chr12-110240852; COSMIC: COSV99924528;