rs55728855

Variant names:

• chr12-109783719-C-T
• rs55728855
• NM_021625.5:c.2518G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021625.5(TRPV4):​c.2518G>A​(p.Glu840Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0101 in 1,613,748 control chromosomes in the GnomAD database, including 104 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (6 hom., cov: 32)
  • Exomes 𝑓: 0.010 (98 hom.)
• Consequence: TRPV4 NM_021625.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 5.34
• Publications: 17 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=0.0075240433).
• BP6: Variant 12-109783719-C-T is Benign according to our data. Variant chr12-109783719-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 137726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00694 (1057/152200) while in subpopulation NFE AF = 0.0116 (787/68002). AF 95% confidence interval is 0.0109. There are 6 homozygotes in GnomAd4. There are 505 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1057 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPV4	NM_021625.5	c.2518G>A	p.Glu840Lys	missense_variant	Exon 16 of 16	ENST00000261740.7	NP_067638.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPV4	ENST00000261740.7	c.2518G>A	p.Glu840Lys	missense_variant	Exon 16 of 16	1	NM_021625.5	ENSP00000261740.2

Frequencies

GnomAD3 genomes AF: 0.00695 AC: 1057 AN: 152082 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.00857

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0116

Gnomad OTH AF: 0.00764

GnomAD2 exomes AF: 0.00645 AC: 1617 AN: 250750 AF XY: 0.00667

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.000696

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00955

Gnomad NFE exome AF: 0.00966

Gnomad OTH exome AF: 0.00800

GnomAD4 exome AF: 0.0104 AC: 15168 AN: 1461548 Hom.: 98 Cov.: 31 AF XY: 0.0102 AC XY: 7406 AN XY: 727056

African (AFR) AF: 0.00146 AC: 49 AN: 33480

American (AMR) AF: 0.00241 AC: 108 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000804 AC: 21 AN: 26134

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39698

South Asian (SAS) AF: 0.00568 AC: 490 AN: 86258

European-Finnish (FIN) AF: 0.0102 AC: 544 AN: 53096

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.0120 AC: 13349 AN: 1112002

Other (OTH) AF: 0.00974 AC: 588 AN: 60390

GnomAD4 genome AF: 0.00694 AC: 1057 AN: 152200 Hom.: 6 Cov.: 32 AF XY: 0.00679 AC XY: 505 AN XY: 74386

African (AFR) AF: 0.00219 AC: 91 AN: 41516

American (AMR) AF: 0.00275 AC: 42 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5168

South Asian (SAS) AF: 0.00395 AC: 19 AN: 4814

European-Finnish (FIN) AF: 0.00857 AC: 91 AN: 10614

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0116 AC: 787 AN: 68002

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.00890 Hom.: 22

Bravo AF: 0.00575

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.00953 AC: 82

ExAC AF: 0.00629 AC: 764

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00916

EpiControl AF: 0.00895

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

May 06, 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. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 13, 2015

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

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

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

- -

Jul 31, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 15, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TRPV4: BP4, BS1, BS2 -

Charcot-Marie-Tooth disease axonal type 2C Benign:3

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 27, 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

- -

Inborn genetic diseases Benign:1

Aug 30, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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. -

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. -

Connective tissue disorder Benign:1

Aug 24, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;T;.;.;.;.
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.95	.;D;D;D;D;D
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.0075	T;T;T;T;T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.9	L;L;.;.;.;.
PhyloP100		5.3
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.6	N;N;N;N;N;N
REVEL	Benign	0.28
Sift	Uncertain	0.0070	D;D;D;D;D;D
Sift4G	Uncertain	0.022	D;D;D;D;D;D
Polyphen		0.85	P;P;P;P;P;P
Vest4		0.23
MVP		0.95
MPC		1.1
ClinPred		0.045	T
GERP RS		5.4
Varity_R		0.16
gMVP		0.46
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs55728855; hg19: chr12-110221524;