rs10774894

Variant names:

• chr12-109783826-G-C
• rs10774894
• NM_021625.5:c.2459-48C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-109783826-G-C
• chr12-109783826-G-A
• chr12-109783826-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021625.5(TRPV4):​c.2459-48C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 1,601,946 control chromosomes in the GnomAD database, including 209,442 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (19167 hom., cov: 28)
  • Exomes 𝑓: 0.51 (190275 hom.)
• Consequence: TRPV4 NM_021625.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.34
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 12-109783826-G-C is Benign according to our data. Variant chr12-109783826-G-C is described in ClinVar as Benign. ClinVar VariationId is 261417.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.735 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.2459-48C>G		intron	N/A	NP_067638.3
	TRPV4	NM_001177431.1		c.2357-48C>G		intron	N/A	NP_001170902.1	Q9HBA0-5
	TRPV4	NM_001177428.1		c.2318-48C>G		intron	N/A	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.2459-48C>G		intron	N/A	ENSP00000261740.2	Q9HBA0-1
	TRPV4	ENST00000418703.7	TSL:1	c.2459-48C>G		intron	N/A	ENSP00000406191.2	Q9HBA0-1
	TRPV4	ENST00000536838.1	TSL:1	c.2357-48C>G		intron	N/A	ENSP00000444336.1	Q9HBA0-5

Frequencies

GnomAD3 genomes AF: 0.500 AC: 75641 AN: 151374 Hom.: 19144 Cov.: 28

Gnomad AFR AF: 0.443

Gnomad AMI AF: 0.573

Gnomad AMR AF: 0.531

Gnomad ASJ AF: 0.523

Gnomad EAS AF: 0.755

Gnomad SAS AF: 0.643

Gnomad FIN AF: 0.497

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.495

Gnomad OTH AF: 0.522

GnomAD2 exomes AF: 0.536 AC: 129580 AN: 241558 AF XY: 0.543

Gnomad AFR exome AF: 0.444

Gnomad AMR exome AF: 0.498

Gnomad ASJ exome AF: 0.523

Gnomad EAS exome AF: 0.748

Gnomad FIN exome AF: 0.518

Gnomad NFE exome AF: 0.504

Gnomad OTH exome AF: 0.534

GnomAD4 exome AF: 0.509 AC: 738072 AN: 1450454 Hom.: 190275 Cov.: 34 AF XY: 0.514 AC XY: 370643 AN XY: 721694

African (AFR) AF: 0.443 AC: 14824 AN: 33436

American (AMR) AF: 0.497 AC: 22132 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.517 AC: 13429 AN: 25976

East Asian (EAS) AF: 0.757 AC: 30019 AN: 39674

South Asian (SAS) AF: 0.635 AC: 54578 AN: 85996

European-Finnish (FIN) AF: 0.512 AC: 22975 AN: 44856

Middle Eastern (MID) AF: 0.591 AC: 3402 AN: 5756

European-Non Finnish (NFE) AF: 0.492 AC: 545880 AN: 1109990

Other (OTH) AF: 0.512 AC: 30833 AN: 60196

GnomAD4 genome AF: 0.500 AC: 75705 AN: 151492 Hom.: 19167 Cov.: 28 AF XY: 0.507 AC XY: 37541 AN XY: 74008

African (AFR) AF: 0.443 AC: 18283 AN: 41274

American (AMR) AF: 0.530 AC: 8064 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.523 AC: 1816 AN: 3470

East Asian (EAS) AF: 0.755 AC: 3830 AN: 5072

South Asian (SAS) AF: 0.644 AC: 3080 AN: 4784

European-Finnish (FIN) AF: 0.497 AC: 5236 AN: 10536

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.495 AC: 33608 AN: 67830

Other (OTH) AF: 0.524 AC: 1106 AN: 2110

Alfa AF: 0.419 Hom.: 2164

Bravo AF: 0.497

Asia WGS AF: 0.643 AC: 2231 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.055
DANN	Benign	0.54
PhyloP100		-1.3
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: rs10774894; hg19: chr12-110221631; COSMIC: COSV55684023;