12-109792316-G-A

Variant names:

• chr12-109792316-G-A
• rs145460865
• NM_021625.5:c.1891+47C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021625.5(TRPV4):​c.1891+47C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00566 in 1,528,462 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (3 hom., cov: 31)
  • Exomes 𝑓: 0.0058 (51 hom.)
• Consequence: TRPV4 NM_021625.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0680
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-109792316-G-A is Benign according to our data. Variant chr12-109792316-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 261416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00468 (703/150198) while in subpopulation NFE AF = 0.00706 (478/67742). AF 95% confidence interval is 0.00653. There are 3 homozygotes in GnomAd4. There are 341 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 703 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPV4	NM_021625.5	MANE Select	c.1891+47C>T		intron	N/A	NP_067638.3
	TRPV4	NM_001177431.1		c.1789+47C>T		intron	N/A	NP_001170902.1
	TRPV4	NM_001177428.1		c.1750+47C>T		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.1891+47C>T		intron	N/A	ENSP00000261740.2
	TRPV4	ENST00000418703.7	TSL:1	c.1891+47C>T		intron	N/A	ENSP00000406191.2
	TRPV4	ENST00000536838.1	TSL:1	c.1789+47C>T		intron	N/A	ENSP00000444336.1

Frequencies

GnomAD3 genomes AF: 0.00468 AC: 703 AN: 150146 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.000933

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.00166

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.000587

Gnomad SAS AF: 0.00126

Gnomad FIN AF: 0.0137

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.00706

Gnomad OTH AF: 0.00290

GnomAD2 exomes AF: 0.00585 AC: 1451 AN: 248022 AF XY: 0.00589

Gnomad AFR exome AF: 0.000635

Gnomad AMR exome AF: 0.00213

Gnomad ASJ exome AF: 0.000301

Gnomad EAS exome AF: 0.000328

Gnomad FIN exome AF: 0.0114

Gnomad NFE exome AF: 0.00914

Gnomad OTH exome AF: 0.00577

GnomAD4 exome AF: 0.00576 AC: 7944 AN: 1378264 Hom.: 51 Cov.: 26 AF XY: 0.00569 AC XY: 3921 AN XY: 689254

African (AFR) AF: 0.000887 AC: 28 AN: 31580

American (AMR) AF: 0.00223 AC: 98 AN: 43938

Ashkenazi Jewish (ASJ) AF: 0.000198 AC: 5 AN: 25272

East Asian (EAS) AF: 0.000235 AC: 9 AN: 38346

South Asian (SAS) AF: 0.00187 AC: 158 AN: 84436

European-Finnish (FIN) AF: 0.0115 AC: 592 AN: 51574

Middle Eastern (MID) AF: 0.00653 AC: 36 AN: 5516

European-Non Finnish (NFE) AF: 0.00646 AC: 6719 AN: 1040284

Other (OTH) AF: 0.00522 AC: 299 AN: 57318

GnomAD4 genome AF: 0.00468 AC: 703 AN: 150198 Hom.: 3 Cov.: 31 AF XY: 0.00466 AC XY: 341 AN XY: 73188

African (AFR) AF: 0.000931 AC: 38 AN: 40808

American (AMR) AF: 0.00166 AC: 25 AN: 15038

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3466

East Asian (EAS) AF: 0.000589 AC: 3 AN: 5096

South Asian (SAS) AF: 0.00126 AC: 6 AN: 4746

European-Finnish (FIN) AF: 0.0137 AC: 137 AN: 10016

Middle Eastern (MID) AF: 0.00347 AC: 1 AN: 288

European-Non Finnish (NFE) AF: 0.00706 AC: 478 AN: 67742

Other (OTH) AF: 0.00287 AC: 6 AN: 2088

Alfa AF: 0.00488 Hom.: 1

Bravo AF: 0.00373

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 27, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	9.2
DANN	Benign	0.42
PhyloP100		-0.068
Mutation Taster		=100/0	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: rs145460865; hg19: chr12-110230121;