rs776163103

Variant names:

• chr12-109814771-C-A
• rs776163103
• NM_021625.5:c.26G>T

Your query was ambiguous. Multiple possible variants found:

• chr12-109814771-C-A
• chr12-109814771-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021625.5(TRPV4):​c.26G>T​(p.Arg9Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,397,322 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R9H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: TRPV4 NM_021625.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.190
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06988865).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPV4	NM_021625.5	c.26G>T	p.Arg9Leu	missense_variant	Exon 2 of 16	ENST00000261740.7	NP_067638.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPV4	ENST00000261740.7	c.26G>T	p.Arg9Leu	missense_variant	Exon 2 of 16	1	NM_021625.5	ENSP00000261740.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1397322 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 690256

African (AFR) AF: 0.00 AC: 0 AN: 31784

American (AMR) AF: 0.00 AC: 0 AN: 36170

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25228

East Asian (EAS) AF: 0.00 AC: 0 AN: 36050

South Asian (SAS) AF: 0.00 AC: 0 AN: 79964

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42642

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5068

European-Non Finnish (NFE) AF: 9.24e-7 AC: 1 AN: 1082318

Other (OTH) AF: 0.00 AC: 0 AN: 58098

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	8.9
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T;T;.;.;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.82	.;T;T;T;T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.070	T;T;T;T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	0.34	N;N;N;N;N;N
PhyloP100		-0.19
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.56	N;N;N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.047	D;D;T;D;T;T
Sift4G	Benign	0.10	T;T;T;T;T;D
Polyphen		0.020	B;B;B;B;B;B
Vest4		0.063
MutPred		0.23		Gain of catalytic residue at G11 (P = 0.0047);Gain of catalytic residue at G11 (P = 0.0047);Gain of catalytic residue at G11 (P = 0.0047);Gain of catalytic residue at G11 (P = 0.0047);Gain of catalytic residue at G11 (P = 0.0047);Gain of catalytic residue at G11 (P = 0.0047);
MVP		0.70
MPC		0.49
ClinPred		0.046	T
GERP RS		1.6
PromoterAI		0.0022	Neutral
Varity_R		0.050
gMVP		0.18
Mutation Taster		=97/3	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: rs776163103; hg19: chr12-110252576;