rs3742030

Positions:

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

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P19P) has been classified as Benign.

• 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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TRPV4. . Gene score misZ 1.9225 (greater than the threshold 3.09). Trascript score misZ 3.5609 (greater than threshold 3.09). GenCC has associacion of gene with TRPV4-related bone disorder, metatropic dysplasia, Charcot-Marie-Tooth disease axonal type 2C, spondylometaphyseal dysplasia, Kozlowski type, familial avascular necrosis of femoral head, parastremmatic dwarfism, neuromuscular disease, autosomal dominant brachyolmia, familial digital arthropathy-brachydactyly, neuronopathy, distal hereditary motor, autosomal dominant 8, scapuloperoneal spinal muscular atrophy, autosomal dominant.
• 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. Variant chr12-109814742-G-A is described in Lovd as [Benign]. Variant chr12-109814742-G-A is described in Lovd as [Likely_benign].
• 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/exons	MANE	Protein	UniProt
TRPV4	NM_021625.5	c.55C>T	p.Pro19Ser	missense_variant	2/16	ENST00000261740.7	NP_067638.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPV4	ENST00000261740.7	c.55C>T	p.Pro19Ser	missense_variant	2/16	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

GnomAD3 exomes AF: 0.0365 AC: 7054 AN: 193106 Hom.: 151 AF XY: 0.0376 AC XY: 3958 AN XY: 105360

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 SAS exome AF: 0.0578

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

Gnomad4 AFR exome AF: 0.0469

Gnomad4 AMR exome AF: 0.0297

Gnomad4 ASJ exome AF: 0.0152

Gnomad4 EAS exome AF: 0.0627

Gnomad4 SAS exome AF: 0.0547

Gnomad4 FIN exome AF: 0.0438

Gnomad4 NFE exome AF: 0.0259

Gnomad4 OTH exome AF: 0.0333

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

Gnomad4 AFR AF: 0.0450

Gnomad4 AMR AF: 0.0302

Gnomad4 ASJ AF: 0.0138

Gnomad4 EAS AF: 0.0591

Gnomad4 SAS AF: 0.0506

Gnomad4 FIN AF: 0.0466

Gnomad4 NFE AF: 0.0274

Gnomad4 OTH AF: 0.0411

Alfa AF: 0.0305 Hom.: 17

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

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 02, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 28, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Neuronopathy, distal hereditary motor, autosomal dominant 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 01, 2022

- -

Sodium serum level quantitative trait locus 1 Other:1

association, no assertion criteria provided

literature only

OMIM

Aug 18, 2009

- -

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
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
Varity_R		0.034
gMVP		0.26

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

Publications

LitVar

Other links and lift over

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