12-109808459-C-T

Variant names:

• chr12-109808459-C-T
• rs114101785
• NM_021625.5:c.396G>A

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.396G>A​(p.Pro132Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000466 in 1,612,212 control chromosomes in the GnomAD database, including 4 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. P132P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (4 hom.)
• Consequence: TRPV4 NM_021625.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.73
• Publications: 2 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 12-109808459-C-T is Benign according to our data. Variant chr12-109808459-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 241388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.73 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00262 (398/152166) while in subpopulation AFR AF = 0.00925 (384/41522). AF 95% confidence interval is 0.00849. There are 0 homozygotes in GnomAd4. There are 172 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 398 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.396G>A	p.Pro132Pro	synonymous	Exon 3 of 16	NP_067638.3
	TRPV4	NM_001177431.1		c.294G>A	p.Pro98Pro	synonymous	Exon 3 of 16	NP_001170902.1	Q9HBA0-5
	TRPV4	NM_001177428.1		c.396G>A	p.Pro132Pro	synonymous	Exon 2 of 14	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.396G>A	p.Pro132Pro	synonymous	Exon 3 of 16	ENSP00000261740.2	Q9HBA0-1
	TRPV4	ENST00000418703.7	TSL:1	c.396G>A	p.Pro132Pro	synonymous	Exon 2 of 15	ENSP00000406191.2	Q9HBA0-1
	TRPV4	ENST00000536838.1	TSL:1	c.294G>A	p.Pro98Pro	synonymous	Exon 3 of 16	ENSP00000444336.1	Q9HBA0-5

Frequencies

GnomAD3 genomes AF: 0.00262 AC: 399 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00930

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

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: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000524 AC: 130 AN: 248154 AF XY: 0.000297

Gnomad AFR exome AF: 0.00738

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000898

Gnomad OTH exome AF: 0.000659

GnomAD4 exome AF: 0.000242 AC: 353 AN: 1460046 Hom.: 4 Cov.: 32 AF XY: 0.000187 AC XY: 136 AN XY: 725956

African (AFR) AF: 0.00864 AC: 289 AN: 33450

American (AMR) AF: 0.000336 AC: 15 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39660

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.000354 AC: 2 AN: 5654

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1110666

Other (OTH) AF: 0.000464 AC: 28 AN: 60282

GnomAD4 genome AF: 0.00262 AC: 398 AN: 152166 Hom.: 0 Cov.: 32 AF XY: 0.00231 AC XY: 172 AN XY: 74388

African (AFR) AF: 0.00925 AC: 384 AN: 41522

American (AMR) AF: 0.000459 AC: 7 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68000

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.000179 Hom.: 0

Bravo AF: 0.00294

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease axonal type 2C (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	1.2
DANN	Benign	0.72
PhyloP100		-3.7
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: rs114101785; hg19: chr12-110246264; COSMIC: COSV99924248;