rs3742034

Variant names:

• chr12-109800682-A-G
• rs3742034
• NM_021625.5:c.789T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_021625.5(TRPV4):​c.789T>C​(p.Asp263Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0992 in 1,614,032 control chromosomes in the GnomAD database, including 9,275 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1585 hom., cov: 32)
  • Exomes 𝑓: 0.096 (7690 hom.)
• Consequence: TRPV4 NM_021625.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -1.76

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-109800682-A-G is Benign according to our data. Variant chr12-109800682-A-G is described in ClinVar as [Benign]. Clinvar id is 137722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109800682-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.76 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPV4	NM_021625.5	c.789T>C	p.Asp263Asp	synonymous_variant	Exon 5 of 16	ENST00000261740.7	NP_067638.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPV4	ENST00000261740.7	c.789T>C	p.Asp263Asp	synonymous_variant	Exon 5 of 16	1	NM_021625.5	ENSP00000261740.2

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19325 AN: 152126 Hom.: 1578 Cov.: 32

Gnomad AFR AF: 0.222

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.0565

Gnomad EAS AF: 0.0652

Gnomad SAS AF: 0.188

Gnomad FIN AF: 0.0888

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.0860

Gnomad OTH AF: 0.120

GnomAD3 exomes AF: 0.107 AC: 26809 AN: 251264 Hom.: 1812 AF XY: 0.110 AC XY: 14979 AN XY: 135864

Gnomad AFR exome AF: 0.222

Gnomad AMR exome AF: 0.0828

Gnomad ASJ exome AF: 0.0650

Gnomad EAS exome AF: 0.0560

Gnomad SAS exome AF: 0.195

Gnomad FIN exome AF: 0.0912

Gnomad NFE exome AF: 0.0885

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.0962 AC: 140677 AN: 1461788 Hom.: 7690 Cov.: 34 AF XY: 0.0986 AC XY: 71686 AN XY: 727192

Gnomad4 AFR exome AF: 0.224

Gnomad4 AMR exome AF: 0.0834

Gnomad4 ASJ exome AF: 0.0650

Gnomad4 EAS exome AF: 0.0664

Gnomad4 SAS exome AF: 0.191

Gnomad4 FIN exome AF: 0.0909

Gnomad4 NFE exome AF: 0.0871

Gnomad4 OTH exome AF: 0.0997

GnomAD4 genome AF: 0.127 AC: 19380 AN: 152244 Hom.: 1585 Cov.: 32 AF XY: 0.128 AC XY: 9563 AN XY: 74444

Gnomad4 AFR AF: 0.223

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.0565

Gnomad4 EAS AF: 0.0645

Gnomad4 SAS AF: 0.188

Gnomad4 FIN AF: 0.0888

Gnomad4 NFE AF: 0.0860

Gnomad4 OTH AF: 0.124

Alfa AF: 0.100 Hom.: 497

Bravo AF: 0.129

Asia WGS AF: 0.153 AC: 532 AN: 3478

EpiCase AF: 0.0848

EpiControl AF: 0.0876

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 18, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 11, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 18, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Charcot-Marie-Tooth disease axonal type 2C Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Charcot-Marie-Tooth disease Benign:1

-

Molecular Genetics Laboratory, London Health Sciences Centre

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuronopathy, distal hereditary motor, autosomal dominant 8 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Scapuloperoneal spinal muscular atrophy Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Brachyrachia (short spine dysplasia) Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Spondylometaphyseal dysplasia, Kozlowski type Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Metatropic dysplasia Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.32
DANN	Benign	0.40

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: rs3742034; hg19: chr12-110238487; COSMIC: COSV55684128;