NM_021625.5:c.2034C>T

Variant names:

• chr12-109788574-G-A
• rs3742037
• NM_021625.5:c.2034C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_021625.5(TRPV4):​c.2034C>T​(p.Ile678Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,614,170 control chromosomes in the GnomAD database, including 20,663 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1829 hom., cov: 33)
  • Exomes 𝑓: 0.15 (18834 hom.)
• Consequence: TRPV4 NM_021625.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.149
• Publications: 19 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, 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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 12-109788574-G-A is Benign according to our data. Variant chr12-109788574-G-A is described in ClinVar as Benign. ClinVar VariationId is 137725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.149 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.212 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPV4	NM_021625.5	MANE Select	c.2034C>T	p.Ile678Ile	synonymous	Exon 13 of 16	NP_067638.3
	TRPV4	NM_001177431.1		c.1932C>T	p.Ile644Ile	synonymous	Exon 13 of 16	NP_001170902.1	Q9HBA0-5
	TRPV4	NM_001177428.1		c.1893C>T	p.Ile631Ile	synonymous	Exon 11 of 14	NP_001170899.1	Q9HBA0-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPV4	ENST00000261740.7	TSL:1 MANE Select	c.2034C>T	p.Ile678Ile	synonymous	Exon 13 of 16	ENSP00000261740.2	Q9HBA0-1
	TRPV4	ENST00000418703.7	TSL:1	c.2034C>T	p.Ile678Ile	synonymous	Exon 12 of 15	ENSP00000406191.2	Q9HBA0-1
	TRPV4	ENST00000536838.1	TSL:1	c.1932C>T	p.Ile644Ile	synonymous	Exon 13 of 16	ENSP00000444336.1	Q9HBA0-5

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22490 AN: 152168 Hom.: 1826 Cov.: 33

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.0654

Gnomad EAS AF: 0.188

Gnomad SAS AF: 0.223

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.152

GnomAD2 exomes AF: 0.172 AC: 43232 AN: 251470 AF XY: 0.170

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.284

Gnomad ASJ exome AF: 0.0676

Gnomad EAS exome AF: 0.193

Gnomad FIN exome AF: 0.171

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.154 AC: 225820 AN: 1461884 Hom.: 18834 Cov.: 34 AF XY: 0.156 AC XY: 113317 AN XY: 727246

African (AFR) AF: 0.116 AC: 3884 AN: 33480

American (AMR) AF: 0.279 AC: 12460 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0686 AC: 1792 AN: 26136

East Asian (EAS) AF: 0.190 AC: 7551 AN: 39700

South Asian (SAS) AF: 0.229 AC: 19749 AN: 86256

European-Finnish (FIN) AF: 0.171 AC: 9125 AN: 53418

Middle Eastern (MID) AF: 0.106 AC: 613 AN: 5768

European-Non Finnish (NFE) AF: 0.145 AC: 161265 AN: 1112006

Other (OTH) AF: 0.155 AC: 9381 AN: 60396

GnomAD4 genome AF: 0.148 AC: 22501 AN: 152286 Hom.: 1829 Cov.: 33 AF XY: 0.151 AC XY: 11250 AN XY: 74472

African (AFR) AF: 0.116 AC: 4825 AN: 41562

American (AMR) AF: 0.211 AC: 3221 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0654 AC: 227 AN: 3470

East Asian (EAS) AF: 0.188 AC: 972 AN: 5180

South Asian (SAS) AF: 0.223 AC: 1076 AN: 4824

European-Finnish (FIN) AF: 0.168 AC: 1785 AN: 10612

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.146 AC: 9936 AN: 68022

Other (OTH) AF: 0.151 AC: 319 AN: 2116

Alfa AF: 0.143 Hom.: 7481

Bravo AF: 0.150

Asia WGS AF: 0.211 AC: 734 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Charcot-Marie-Tooth disease axonal type 2C (2)
-	-	1	Brachyrachia (short spine dysplasia) (1)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Metatropic dysplasia (1)
-	-	1	Neuronopathy, distal hereditary motor, autosomal dominant 8 (1)
-	-	1	not provided (1)
-	-	1	Scapuloperoneal spinal muscular atrophy (1)
-	-	1	Spondylometaphyseal dysplasia, Kozlowski type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	8.1
DANN	Benign	0.81
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism (auto)

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: rs3742037; hg19: chr12-110226379; COSMIC: COSV55681905;