12-109794355-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP3_ModerateBP6BS2

The NM_021625.5(TRPV4):c.1465G>A(p.Ala489Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,612,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

TRPV4
NM_021625.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 7.78

Publications

6 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: Likely_benign. The variant received -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.855

BP6

Variant 12-109794355-C-T is Benign according to our data. Variant chr12-109794355-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 583175.

BS2

High AC in GnomAdExome4 at 44 AD gene.

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.1465G>A	p.Ala489Thr	missense	Exon 8 of 16	NP_067638.3
TRPV4	NM_001177431.1		c.1363G>A	p.Ala455Thr	missense	Exon 8 of 16	NP_001170902.1	Q9HBA0-5
TRPV4	NM_001177428.1		c.1324G>A	p.Ala442Thr	missense	Exon 6 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.1465G>A	p.Ala489Thr	missense	Exon 8 of 16	ENSP00000261740.2	Q9HBA0-1
TRPV4	ENST00000418703.7	TSL:1	c.1465G>A	p.Ala489Thr	missense	Exon 7 of 15	ENSP00000406191.2	Q9HBA0-1
TRPV4	ENST00000536838.1	TSL:1	c.1363G>A	p.Ala455Thr	missense	Exon 8 of 16	ENSP00000444336.1	Q9HBA0-5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000720

AC:

AN:

249922

AF XY:

0.0000961

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000158

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1460508

Hom.:

Cov.:

AF XY:

0.0000317

AC XY:

AN XY:

726642

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52060

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000306

AC:

AN:

1111998

Other (OTH)

AF:

0.0000662

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41416

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Brachyrachia (short spine dysplasia) (1)

Metatropic dysplasia (1)

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

Scapuloperoneal spinal muscular atrophy (1)

Spondylometaphyseal dysplasia, Kozlowski type (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.85

MetaSVM

Pathogenic

0.83

MutationAssessor

Uncertain

2.8

PhyloP100

7.8

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-3.1

REVEL

Pathogenic

0.82

Sift

Benign

0.075

Sift4G

Benign

0.10

Polyphen

1.0

Vest4

0.94

MutPred

0.57

Gain of catalytic residue at T488 (P = 0.0021)

MVP

0.99

MPC

1.2

ClinPred

0.90

GERP RS

4.5

Varity_R

0.29

gMVP

0.73

Mutation Taster

=40/60

disease causing

(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