rs1344554

Positions:

• chr12-109800676-G-A

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.795C>T​(p.His265=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0572 in 1,614,104 control chromosomes in the GnomAD database, including 4,027 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (854 hom., cov: 32)
  • Exomes 𝑓: 0.054 (3173 hom.)
• Consequence: TRPV4 NM_021625.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.721

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=-0.48).
• BP6: Variant 12-109800676-G-A is Benign according to our data. Variant chr12-109800676-G-A is described in ClinVar as [Benign]. Clinvar id is 137723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-109800676-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.721 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPV4	NM_021625.5	c.795C>T	p.His265=	synonymous_variant	5/16	ENST00000261740.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPV4	ENST00000261740.7	c.795C>T	p.His265=	synonymous_variant	5/16	1	NM_021625.5	P1

Frequencies

GnomAD3 genomes AF: 0.0845 AC: 12858 AN: 152182 Hom.: 852 Cov.: 32

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.0714

Gnomad AMR AF: 0.0894

Gnomad ASJ AF: 0.0685

Gnomad EAS AF: 0.0285

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.0213

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0440

Gnomad OTH AF: 0.0664

GnomAD3 exomes AF: 0.0753 AC: 18929 AN: 251272 Hom.: 1139 AF XY: 0.0723 AC XY: 9826 AN XY: 135858

Gnomad AFR exome AF: 0.164

Gnomad AMR exome AF: 0.154

Gnomad ASJ exome AF: 0.0655

Gnomad EAS exome AF: 0.0267

Gnomad SAS exome AF: 0.140

Gnomad FIN exome AF: 0.0198

Gnomad NFE exome AF: 0.0413

Gnomad OTH exome AF: 0.0677

GnomAD4 exome AF: 0.0543 AC: 79435 AN: 1461804 Hom.: 3173 Cov.: 33 AF XY: 0.0560 AC XY: 40710 AN XY: 727208

Gnomad4 AFR exome AF: 0.166

Gnomad4 AMR exome AF: 0.144

Gnomad4 ASJ exome AF: 0.0634

Gnomad4 EAS exome AF: 0.0249

Gnomad4 SAS exome AF: 0.137

Gnomad4 FIN exome AF: 0.0206

Gnomad4 NFE exome AF: 0.0431

Gnomad4 OTH exome AF: 0.0593

GnomAD4 genome AF: 0.0846 AC: 12883 AN: 152300 Hom.: 854 Cov.: 32 AF XY: 0.0834 AC XY: 6208 AN XY: 74472

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.0896

Gnomad4 ASJ AF: 0.0685

Gnomad4 EAS AF: 0.0286

Gnomad4 SAS AF: 0.143

Gnomad4 FIN AF: 0.0213

Gnomad4 NFE AF: 0.0440

Gnomad4 OTH AF: 0.0658

Alfa AF: 0.0625 Hom.: 236

Bravo AF: 0.0920

Asia WGS AF: 0.105 AC: 365 AN: 3478

EpiCase AF: 0.0458

EpiControl AF: 0.0443

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2017	- -

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

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- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

Brachyrachia (short spine dysplasia) Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	-0.48
CADD	Benign	2.2
DANN	Benign	0.49

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: rs1344554; hg19: chr12-110238481; COSMIC: COSV55682452;