NM_021625.5:c.1713C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_021625.5(TRPV4):c.1713C>G(p.Ile571Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0029 in 1,614,044 control chromosomes in the GnomAD database, including 204 homozygotes. 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I571I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0070 ( 57 hom., cov: 31)

Exomes 𝑓: 0.0025 ( 147 hom. )

Consequence

TRPV4
NM_021625.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.577

Publications

3 publications found

Variant links:

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, ClinGen
neuromuscular disease
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
spondylometaphyseal dysplasia, Kozlowski type
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, 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), Genomics England PanelApp, Orphanet
Charcot-Marie-Tooth disease axonal type 2C
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
brachyolmia
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
scapuloperoneal spinal muscular atrophy, autosomal dominant
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
spondyloepimetaphyseal dysplasia, Maroteaux type
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
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

TRPV4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0025081635).

BP6

Variant 12-109792763-G-C is Benign according to our data. Variant chr12-109792763-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0632 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021625.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRPV4	NM_021625.5	MANE Select	c.1713C>G	p.Ile571Met	missense	Exon 11 of 16	NP_067638.3
TRPV4	NM_001177431.1		c.1611C>G	p.Ile537Met	missense	Exon 11 of 16	NP_001170902.1	Q9HBA0-5
TRPV4	NM_001177428.1		c.1572C>G	p.Ile524Met	missense	Exon 9 of 14	NP_001170899.1	Q9HBA0-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRPV4	ENST00000261740.7	TSL:1 MANE Select	c.1713C>G	p.Ile571Met	missense	Exon 11 of 16	ENSP00000261740.2	Q9HBA0-1
TRPV4	ENST00000418703.7	TSL:1	c.1713C>G	p.Ile571Met	missense	Exon 10 of 15	ENSP00000406191.2	Q9HBA0-1
TRPV4	ENST00000536838.1	TSL:1	c.1611C>G	p.Ile537Met	missense	Exon 11 of 16	ENSP00000444336.1	Q9HBA0-5

Frequencies

GnomAD3 genomes

AF:

0.00702

AC:

1068

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0667

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00909

GnomAD2 exomes

AF:

0.0107

AC:

2699

AN:

251150

AF XY:

0.00777

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0762

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.00718

GnomAD4 exome

AF:

0.00247

AC:

3610

AN:

1461776

Hom.:

147

Cov.:

AF XY:

0.00204

AC XY:

1486

AN XY:

727184

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

33480

American (AMR)

AF:

0.0755

AC:

3377

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000139

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53328

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000558

AC:

AN:

1112008

Other (OTH)

AF:

0.00232

AC:

140

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

232

464

695

927

1159

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

174

232

290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00701

AC:

1067

AN:

152268

Hom.:

Cov.:

AF XY:

0.00857

AC XY:

638

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.000505

AC:

AN:

41560

American (AMR)

AF:

0.0666

AC:

1018

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68014

Other (OTH)

AF:

0.00900

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

103

155

206

258

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000784

Hom.:

Bravo

AF:

0.0104

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00759

AC:

921

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Charcot-Marie-Tooth disease axonal type 2C (2)

Brachyrachia (short spine dysplasia) (1)

Charcot-Marie-Tooth disease (1)

Connective tissue disorder (1)

Metatropic dysplasia (1)

Neuronopathy, distal hereditary motor, autosomal dominant 8 (1)

not specified (1)

Scapuloperoneal spinal muscular atrophy (1)

Spondylometaphyseal dysplasia, Kozlowski type (1)

TRPV4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.18

CADD

Benign

8.4

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.59

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0025

MetaSVM

Uncertain

0.59

MutationAssessor

Benign

1.9

PhyloP100

-0.58

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.18

REVEL

Uncertain

0.50

Sift

Benign

0.15

Sift4G

Benign

0.22

Polyphen

1.0

Vest4

0.47

MPC

1.8

ClinPred

0.029

GERP RS

-12

Varity_R

0.033

gMVP

0.43

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over