dbSNP rs115861965: TRPV4:p.Pro51Leu (chr12-109814645-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_021625.5(TRPV4):c.152C>T(p.Pro51Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,613,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P51Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000091 ( 0 hom. )

Consequence

TRPV4
NM_021625.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 2.05

Publications

4 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=0.028507024).

BP6

Variant 12-109814645-G-A is Benign according to our data. Variant chr12-109814645-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 215917.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000407 (62/152298) while in subpopulation AFR AF = 0.00128 (53/41562). AF 95% confidence interval is 0.001. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 62 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.152C>T	p.Pro51Leu	missense	Exon 2 of 16	NP_067638.3
TRPV4	NM_001177428.1		c.152C>T	p.Pro51Leu	missense	Exon 1 of 14	NP_001170899.1	Q9HBA0-4
TRPV4	NM_147204.2		c.152C>T	p.Pro51Leu	missense	Exon 1 of 14	NP_671737.1	Q9HBA0-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRPV4	ENST00000261740.7	TSL:1 MANE Select	c.152C>T	p.Pro51Leu	missense	Exon 2 of 16	ENSP00000261740.2	Q9HBA0-1
TRPV4	ENST00000418703.7	TSL:1	c.152C>T	p.Pro51Leu	missense	Exon 1 of 15	ENSP00000406191.2	Q9HBA0-1
TRPV4	ENST00000541794.5	TSL:1	c.152C>T	p.Pro51Leu	missense	Exon 1 of 14	ENSP00000442167.1	Q9HBA0-4

Frequencies

GnomAD3 genomes

AF:

0.000407

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000152

AC:

AN:

249236

AF XY:

0.000111

show subpopulations

Gnomad AFR exome

AF:

0.00112

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000533

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000910

AC:

133

AN:

1461388

Hom.:

Cov.:

AF XY:

0.0000949

AC XY:

AN XY:

726996

show subpopulations

African (AFR)

AF:

0.00203

AC:

AN:

33472

American (AMR)

AF:

0.000336

AC:

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53122

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000270

AC:

AN:

1111926

Other (OTH)

AF:

0.000215

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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:

0.000407

AC:

AN:

152298

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00128

AC:

AN:

41562

American (AMR)

AF:

0.000327

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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:

0.000301

Hom.:

Bravo

AF:

0.000461

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

not specified (2)

Brachyrachia (short spine dysplasia) (1)

Inborn genetic diseases (1)

Metatropic dysplasia (1)

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

not provided (1)

Scapuloperoneal spinal muscular atrophy (1)

Spondylometaphyseal dysplasia, Kozlowski type (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.60

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.71

M_CAP

Uncertain

0.29

MetaRNN

Benign

0.029

MetaSVM

Benign

-0.51

MutationAssessor

Benign

0.69

PhyloP100

2.0

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-2.3

REVEL

Benign

0.14

Sift

Benign

0.042

Sift4G

Uncertain

0.055

Polyphen

0.41

Vest4

0.095

MVP

0.80

MPC

0.53

ClinPred

0.029

GERP RS

3.0

PromoterAI

0.018

Neutral

(source)

Varity_R

0.037

gMVP

0.17

Mutation Taster

=65/35

polymorphism

(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