rs57316123

Variant names:

• chr12-109794479-G-A
• rs57316123
• NM_021625.5:c.1341C>T

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.1341C>T​(p.His447His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,613,832 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (6 hom.)
• Consequence: TRPV4 NM_021625.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.760
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 12-109794479-G-A is Benign according to our data. Variant chr12-109794479-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241380.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.76 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00639 (972/152202) while in subpopulation AFR AF = 0.0221 (917/41526). AF 95% confidence interval is 0.0209. There are 6 homozygotes in GnomAd4. There are 475 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 972 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.1341C>T	p.His447His	synonymous	Exon 8 of 16	NP_067638.3
	TRPV4	NM_001177431.1		c.1239C>T	p.His413His	synonymous	Exon 8 of 16	NP_001170902.1
	TRPV4	NM_001177428.1		c.1200C>T	p.His400His	synonymous	Exon 6 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.1341C>T	p.His447His	synonymous	Exon 8 of 16	ENSP00000261740.2
	TRPV4	ENST00000418703.7	TSL:1	c.1341C>T	p.His447His	synonymous	Exon 7 of 15	ENSP00000406191.2
	TRPV4	ENST00000536838.1	TSL:1	c.1239C>T	p.His413His	synonymous	Exon 8 of 16	ENSP00000444336.1

Frequencies

GnomAD3 genomes AF: 0.00630 AC: 958 AN: 152084 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00167 AC: 420 AN: 251164 AF XY: 0.00114

Gnomad AFR exome AF: 0.0223

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000649 AC: 949 AN: 1461630 Hom.: 6 Cov.: 32 AF XY: 0.000561 AC XY: 408 AN XY: 727116

African (AFR) AF: 0.0220 AC: 736 AN: 33474

American (AMR) AF: 0.00121 AC: 54 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53230

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0000378 AC: 42 AN: 1111958

Other (OTH) AF: 0.00157 AC: 95 AN: 60390

GnomAD4 genome AF: 0.00639 AC: 972 AN: 152202 Hom.: 6 Cov.: 32 AF XY: 0.00638 AC XY: 475 AN XY: 74402

African (AFR) AF: 0.0221 AC: 917 AN: 41526

American (AMR) AF: 0.00248 AC: 38 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5154

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67998

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00300 Hom.: 2

Bravo AF: 0.00730

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Charcot-Marie-Tooth disease axonal type 2C (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Brachyrachia (short spine dysplasia) (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Metatropic dysplasia (1)
-	-	1	Neuronopathy, distal hereditary motor, autosomal dominant 8 (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	-0.57
CADD	Benign	5.3
DANN	Benign	0.77
PhyloP100		-0.76
Mutation Taster		=98/2	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: rs57316123; hg19: chr12-110232284;