rs115976458

Variant names:

• chr12-109793968-T-C
• rs115976458
• NM_021625.5:c.1546A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_021625.5(TRPV4):​c.1546A>G​(p.Ile516Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 1,610,516 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: TRPV4 NM_021625.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:13
• Conservation: PhyloP100: 0.566
• Publications: 5 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
• neuromuscular disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• spondylometaphyseal dysplasia, Kozlowski type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: 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), Orphanet, Genomics England PanelApp
• Charcot-Marie-Tooth disease axonal type 2C

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• scapuloperoneal spinal muscular atrophy, autosomal dominant

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03452322).
• BP6: Variant 12-109793968-T-C is Benign according to our data. Variant chr12-109793968-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 215918.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000342 (52/152012) while in subpopulation AMR AF = 0.00111 (17/15282). AF 95% confidence interval is 0.000708. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 52 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPV4	NM_021625.5	MANE Select	c.1546A>G	p.Ile516Val	missense	Exon 9 of 16	NP_067638.3
	TRPV4	NM_001177431.1		c.1444A>G	p.Ile482Val	missense	Exon 9 of 16	NP_001170902.1
	TRPV4	NM_001177428.1		c.1405A>G	p.Ile469Val	missense	Exon 7 of 14	NP_001170899.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPV4	ENST00000261740.7	TSL:1 MANE Select	c.1546A>G	p.Ile516Val	missense	Exon 9 of 16	ENSP00000261740.2
	TRPV4	ENST00000418703.7	TSL:1	c.1546A>G	p.Ile516Val	missense	Exon 8 of 15	ENSP00000406191.2
	TRPV4	ENST00000536838.1	TSL:1	c.1444A>G	p.Ile482Val	missense	Exon 9 of 16	ENSP00000444336.1

Frequencies

GnomAD3 genomes AF: 0.000356 AC: 54 AN: 151894 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000156 AC: 38 AN: 242862 AF XY: 0.000130

Gnomad AFR exome AF: 0.000387

Gnomad AMR exome AF: 0.000589

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000285

Gnomad NFE exome AF: 0.0000274

Gnomad OTH exome AF: 0.000343

GnomAD4 exome AF: 0.000128 AC: 186 AN: 1458504 Hom.: 1 Cov.: 34 AF XY: 0.000120 AC XY: 87 AN XY: 725016

African (AFR) AF: 0.00164 AC: 55 AN: 33470

American (AMR) AF: 0.000495 AC: 22 AN: 44420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25852

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84936

European-Finnish (FIN) AF: 0.000245 AC: 13 AN: 52992

Middle Eastern (MID) AF: 0.00382 AC: 22 AN: 5758

European-Non Finnish (NFE) AF: 0.0000486 AC: 54 AN: 1111242

Other (OTH) AF: 0.000315 AC: 19 AN: 60234

GnomAD4 genome AF: 0.000342 AC: 52 AN: 152012 Hom.: 0 Cov.: 31 AF XY: 0.000350 AC XY: 26 AN XY: 74306

African (AFR) AF: 0.000699 AC: 29 AN: 41486

American (AMR) AF: 0.00111 AC: 17 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67928

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000183 Hom.: 0

Bravo AF: 0.000374

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000132 AC: 16

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	Charcot-Marie-Tooth disease axonal type 2C (2)
-	-	2	not specified (2)
-	-	1	Brachyrachia (short spine dysplasia) (1)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Metatropic dysplasia (1)
-	-	1	Neuronopathy, distal hereditary motor, autosomal dominant 8 (1)
-	-	1	Scapuloperoneal spinal muscular atrophy (1)
-	-	1	Spondylometaphyseal dysplasia, Kozlowski type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Uncertain	0.65	D
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.57
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.24
Sift	Benign	0.33	T
Sift4G	Benign	0.18	T
Polyphen		0.0010	B
Vest4		0.24
MVP		0.84
MPC		0.33
ClinPred		0.012	T
GERP RS		1.9
Varity_R		0.054
gMVP		0.33
Mutation Taster		=76/24	polymorphism

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: rs115976458; hg19: chr12-110231773;