12-109784341-C-G

Variant names:

• chr12-109784341-C-G
• rs34071623
• NM_021625.5:c.2433G>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.2433G>C​(p.Ser811Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00936 in 1,614,148 control chromosomes in the GnomAD database, including 140 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. S811S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0071 (11 hom., cov: 31)
  • Exomes 𝑓: 0.0096 (129 hom.)
• Consequence: TRPV4 NM_021625.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -1.57
• Publications: 4 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: G2P, ClinGen, Orphanet
• neuromuscular disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• spondylometaphyseal dysplasia, Kozlowski type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen
• TRPV4-related bone disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina, ClinGen
• 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: Orphanet, Labcorp Genetics (formerly Invitae)
• brachyolmia

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• scapuloperoneal spinal muscular atrophy, autosomal dominant

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• 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=-0.61).
• BP6: Variant 12-109784341-C-G is Benign according to our data. Variant chr12-109784341-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 219845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.57 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00706 (1075/152284) while in subpopulation SAS AF = 0.0197 (95/4822). AF 95% confidence interval is 0.0165. There are 11 homozygotes in GnomAd4. There are 500 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1075 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.2433G>C	p.Ser811Ser	synonymous	Exon 15 of 16	NP_067638.3
	TRPV4	NM_001177431.1		c.2331G>C	p.Ser777Ser	synonymous	Exon 15 of 16	NP_001170902.1	Q9HBA0-5
	TRPV4	NM_001177428.1		c.2292G>C	p.Ser764Ser	synonymous	Exon 13 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.2433G>C	p.Ser811Ser	synonymous	Exon 15 of 16	ENSP00000261740.2	Q9HBA0-1
	TRPV4	ENST00000418703.7	TSL:1	c.2433G>C	p.Ser811Ser	synonymous	Exon 14 of 15	ENSP00000406191.2	Q9HBA0-1
	TRPV4	ENST00000536838.1	TSL:1	c.2331G>C	p.Ser777Ser	synonymous	Exon 15 of 16	ENSP00000444336.1	Q9HBA0-5

Frequencies

GnomAD3 genomes AF: 0.00706 AC: 1075 AN: 152166 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00523

Gnomad ASJ AF: 0.0409

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0197

Gnomad FIN AF: 0.00235

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00941

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00961 AC: 2416 AN: 251356 AF XY: 0.0104

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00396

Gnomad ASJ exome AF: 0.0429

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.00902

Gnomad OTH exome AF: 0.00898

GnomAD4 exome AF: 0.00960 AC: 14038 AN: 1461864 Hom.: 129 Cov.: 32 AF XY: 0.0100 AC XY: 7304 AN XY: 727238

African (AFR) AF: 0.00116 AC: 39 AN: 33480

American (AMR) AF: 0.00385 AC: 172 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0410 AC: 1072 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0220 AC: 1897 AN: 86258

European-Finnish (FIN) AF: 0.00257 AC: 137 AN: 53400

Middle Eastern (MID) AF: 0.0151 AC: 87 AN: 5768

European-Non Finnish (NFE) AF: 0.00888 AC: 9880 AN: 1112002

Other (OTH) AF: 0.0124 AC: 750 AN: 60396

GnomAD4 genome AF: 0.00706 AC: 1075 AN: 152284 Hom.: 11 Cov.: 31 AF XY: 0.00672 AC XY: 500 AN XY: 74456

African (AFR) AF: 0.00120 AC: 50 AN: 41556

American (AMR) AF: 0.00523 AC: 80 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0409 AC: 142 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.0197 AC: 95 AN: 4822

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00941 AC: 640 AN: 68022

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.0105 Hom.: 5

Bravo AF: 0.00706

Asia WGS AF: 0.0100 AC: 37 AN: 3478

EpiCase AF: 0.00954

EpiControl AF: 0.00972

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	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	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	-0.61
CADD	Benign	0.38
DANN	Benign	0.70
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: rs34071623; hg19: chr12-110222146;