rs35078611

Variant names:

• chr12-109792732-G-A
• rs35078611
• NM_021625.5:c.1744C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-109792732-G-A
• chr12-109792732-G-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_021625.5(TRPV4):​c.1744C>T​(p.Leu582Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000957 in 1,614,150 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L582L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0049 (13 hom., cov: 31)
  • Exomes 𝑓: 0.00054 (7 hom.)
• Consequence: TRPV4 NM_021625.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.63
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 12-109792732-G-A is Benign according to our data. Variant chr12-109792732-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.63 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00493 (751/152318) while in subpopulation AFR AF = 0.0173 (719/41570). AF 95% confidence interval is 0.0162. There are 13 homozygotes in GnomAd4. There are 353 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 751 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.1744C>T	p.Leu582Leu	synonymous	Exon 11 of 16	NP_067638.3
	TRPV4	NM_001177431.1		c.1642C>T	p.Leu548Leu	synonymous	Exon 11 of 16	NP_001170902.1
	TRPV4	NM_001177428.1		c.1603C>T	p.Leu535Leu	synonymous	Exon 9 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.1744C>T	p.Leu582Leu	synonymous	Exon 11 of 16	ENSP00000261740.2
	TRPV4	ENST00000418703.7	TSL:1	c.1744C>T	p.Leu582Leu	synonymous	Exon 10 of 15	ENSP00000406191.2
	TRPV4	ENST00000536838.1	TSL:1	c.1642C>T	p.Leu548Leu	synonymous	Exon 11 of 16	ENSP00000444336.1

Frequencies

GnomAD3 genomes AF: 0.00490 AC: 746 AN: 152200 Hom.: 13 Cov.: 31

Gnomad AFR AF: 0.0172

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00119 AC: 299 AN: 251286 AF XY: 0.000927

Gnomad AFR exome AF: 0.0159

Gnomad AMR exome AF: 0.00107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000543 AC: 794 AN: 1461832 Hom.: 7 Cov.: 33 AF XY: 0.000447 AC XY: 325 AN XY: 727220

African (AFR) AF: 0.0190 AC: 637 AN: 33480

American (AMR) AF: 0.00114 AC: 51 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112004

Other (OTH) AF: 0.00141 AC: 85 AN: 60396

GnomAD4 genome AF: 0.00493 AC: 751 AN: 152318 Hom.: 13 Cov.: 31 AF XY: 0.00474 AC XY: 353 AN XY: 74464

African (AFR) AF: 0.0173 AC: 719 AN: 41570

American (AMR) AF: 0.00183 AC: 28 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00455 Hom.: 4

Bravo AF: 0.00603

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Charcot-Marie-Tooth disease axonal type 2C (2)
-	-	1	Brachyrachia (short spine dysplasia) (1)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Connective tissue disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Metatropic dysplasia (1)
-	-	1	Neuronopathy, distal hereditary motor, autosomal dominant 8 (1)
-	-	1	not specified (1)
-	-	1	Scapuloperoneal spinal muscular atrophy (1)
-	-	1	Spondylometaphyseal dysplasia, Kozlowski type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	4.9
DANN	Benign	0.68
PhyloP100		1.6
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: rs35078611; hg19: chr12-110230537;