rs3742030

Variant names:

• chr12-109814742-G-A
• rs3742030
• NM_021625.5:c.55C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-109814742-G-A
• chr12-109814742-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021625.5(TRPV4):​c.55C>T​(p.Pro19Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0306 in 1,586,158 control chromosomes in the GnomAD database, including 866 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P19H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.035 (105 hom., cov: 32)
  • Exomes 𝑓: 0.030 (761 hom.)
• Consequence: TRPV4 NM_021625.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19 O:1
• Conservation: PhyloP100: 4.97
• Publications: 31 publications found

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 Gene-Disease associations (from GenCC):

• metatropic dysplasia

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• neuromuscular disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• spondylometaphyseal dysplasia, Kozlowski type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• TRPV4-related bone disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• autosomal dominant brachyolmia

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• Charcot-Marie-Tooth disease axonal type 2C

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• scapuloperoneal spinal muscular atrophy, autosomal dominant

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• familial avascular necrosis of femoral head

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial digital arthropathy-brachydactyly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neuronopathy, distal hereditary motor, autosomal dominant 8

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• parastremmatic dwarfism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0023634434).
• BP6: Variant 12-109814742-G-A is Benign according to our data. Variant chr12-109814742-G-A is described in ClinVar as [Benign]. Clinvar id is 5003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPV4	NM_021625.5	c.55C>T	p.Pro19Ser	missense_variant	Exon 2 of 16	ENST00000261740.7	NP_067638.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPV4	ENST00000261740.7	c.55C>T	p.Pro19Ser	missense_variant	Exon 2 of 16	1	NM_021625.5	ENSP00000261740.2

Frequencies

GnomAD3 genomes AF: 0.0355 AC: 5399 AN: 152080 Hom.: 105 Cov.: 32

Gnomad AFR AF: 0.0451

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0303

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.0595

Gnomad SAS AF: 0.0505

Gnomad FIN AF: 0.0466

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0274

Gnomad OTH AF: 0.0415

GnomAD2 exomes AF: 0.0365 AC: 7054 AN: 193106 AF XY: 0.0376

Gnomad AFR exome AF: 0.0456

Gnomad AMR exome AF: 0.0321

Gnomad ASJ exome AF: 0.0149

Gnomad EAS exome AF: 0.0525

Gnomad FIN exome AF: 0.0446

Gnomad NFE exome AF: 0.0277

Gnomad OTH exome AF: 0.0430

GnomAD4 exome AF: 0.0300 AC: 43070 AN: 1433962 Hom.: 761 Cov.: 32 AF XY: 0.0307 AC XY: 21822 AN XY: 711332

African (AFR) AF: 0.0469 AC: 1539 AN: 32844

American (AMR) AF: 0.0297 AC: 1203 AN: 40554

Ashkenazi Jewish (ASJ) AF: 0.0152 AC: 389 AN: 25664

East Asian (EAS) AF: 0.0627 AC: 2393 AN: 38190

South Asian (SAS) AF: 0.0547 AC: 4545 AN: 83048

European-Finnish (FIN) AF: 0.0438 AC: 2138 AN: 48854

Middle Eastern (MID) AF: 0.0635 AC: 358 AN: 5640

European-Non Finnish (NFE) AF: 0.0259 AC: 28531 AN: 1099804

Other (OTH) AF: 0.0333 AC: 1974 AN: 59364

GnomAD4 genome AF: 0.0354 AC: 5395 AN: 152196 Hom.: 105 Cov.: 32 AF XY: 0.0369 AC XY: 2748 AN XY: 74414

African (AFR) AF: 0.0450 AC: 1869 AN: 41536

American (AMR) AF: 0.0302 AC: 462 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3470

East Asian (EAS) AF: 0.0591 AC: 304 AN: 5146

South Asian (SAS) AF: 0.0506 AC: 244 AN: 4824

European-Finnish (FIN) AF: 0.0466 AC: 495 AN: 10616

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0274 AC: 1863 AN: 67978

Other (OTH) AF: 0.0411 AC: 87 AN: 2116

Alfa AF: 0.0311 Hom.: 21

Bravo AF: 0.0352

TwinsUK AF: 0.0224 AC: 83

ALSPAC AF: 0.0322 AC: 124

ESP6500AA AF: 0.0402 AC: 176

ESP6500EA AF: 0.0232 AC: 199

ExAC AF: 0.0319 AC: 3821

Asia WGS AF: 0.0710 AC: 245 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:19 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Jun 05, 2014

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. -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 02, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 28, 2017

Athena Diagnostics

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

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Scapuloperoneal spinal muscular atrophy Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Brachyrachia (short spine dysplasia) Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Spondylometaphyseal dysplasia, Kozlowski type Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Metatropic dysplasia Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Connective tissue disorder Benign:1

Apr 01, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sodium serum level quantitative trait locus 1 Other:1

Aug 18, 2009

OMIM

Significance: association

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;T;.;.;.;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.87	.;D;D;D;D;T
MetaRNN	Benign	0.0024	T;T;T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.90	L;L;L;L;L;L
PhyloP100		5.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.55	N;N;N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.21	T;T;T;T;T;T
Sift4G	Benign	0.46	T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;B
Vest4		0.058
MPC		0.39
ClinPred		0.017	T
GERP RS		3.6
PromoterAI		0.0040	Neutral
Varity_R		0.034
gMVP		0.26
Mutation Taster		=92/8	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3742030; hg19: chr12-110252547; COSMIC: COSV55682218;