12-109807783-A-G

Variant names:

• chr12-109807783-A-G
• rs1861809
• NM_021625.5:c.559+513T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000261740.7(TRPV4):​c.559+513T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.628 in 151,930 control chromosomes in the GnomAD database, including 31,420 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.63 (31420 hom., cov: 31)
• Consequence: TRPV4 ENST00000261740.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.17
• Publications: 11 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.933 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000261740.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPV4	NM_021625.5	MANE Select	c.559+513T>C		intron	N/A	NP_067638.3
	TRPV4	NM_001177431.1		c.457+513T>C		intron	N/A	NP_001170902.1
	TRPV4	NM_001177428.1		c.559+513T>C		intron	N/A	NP_001170899.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPV4	ENST00000261740.7	TSL:1 MANE Select	c.559+513T>C		intron	N/A	ENSP00000261740.2
	TRPV4	ENST00000418703.7	TSL:1	c.559+513T>C		intron	N/A	ENSP00000406191.2
	TRPV4	ENST00000536838.1	TSL:1	c.457+513T>C		intron	N/A	ENSP00000444336.1

Frequencies

GnomAD3 genomes AF: 0.628 AC: 95352 AN: 151812 Hom.: 31355 Cov.: 31

Gnomad AFR AF: 0.761

Gnomad AMI AF: 0.618

Gnomad AMR AF: 0.695

Gnomad ASJ AF: 0.455

Gnomad EAS AF: 0.955

Gnomad SAS AF: 0.786

Gnomad FIN AF: 0.535

Gnomad MID AF: 0.617

Gnomad NFE AF: 0.520

Gnomad OTH AF: 0.599

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.628 AC: 95476 AN: 151930 Hom.: 31420 Cov.: 31 AF XY: 0.636 AC XY: 47197 AN XY: 74260

African (AFR) AF: 0.762 AC: 31564 AN: 41428

American (AMR) AF: 0.696 AC: 10631 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.455 AC: 1574 AN: 3460

East Asian (EAS) AF: 0.956 AC: 4918 AN: 5146

South Asian (SAS) AF: 0.785 AC: 3773 AN: 4804

European-Finnish (FIN) AF: 0.535 AC: 5665 AN: 10580

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.520 AC: 35335 AN: 67920

Other (OTH) AF: 0.603 AC: 1272 AN: 2110

Alfa AF: 0.553 Hom.: 86068

Bravo AF: 0.642

Asia WGS AF: 0.836 AC: 2905 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.64
DANN	Benign	0.72
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1861809; hg19: chr12-110245588;