12-109786742-C-G

Variant names:

• chr12-109786742-C-G
• rs138986228
• NM_021625.5:c.2304G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_021625.5(TRPV4):​c.2304G>C​(p.Ser768Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000492 in 1,613,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S768S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: TRPV4 NM_021625.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:14
• Conservation: PhyloP100: -10.5
• Publications: 0 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-109786742-C-G is Benign according to our data. Variant chr12-109786742-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 499138.
• BP7: Synonymous conserved (PhyloP=-10.5 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000506 (77/152288) while in subpopulation NFE AF = 0.00075 (51/68008). AF 95% confidence interval is 0.000586. There are 0 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 77 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.2304G>C	p.Ser768Ser	synonymous	Exon 14 of 16	NP_067638.3
	TRPV4	NM_001177431.1		c.2202G>C	p.Ser734Ser	synonymous	Exon 14 of 16	NP_001170902.1
	TRPV4	NM_001177428.1		c.2163G>C	p.Ser721Ser	synonymous	Exon 12 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.2304G>C	p.Ser768Ser	synonymous	Exon 14 of 16	ENSP00000261740.2
	TRPV4	ENST00000418703.7	TSL:1	c.2304G>C	p.Ser768Ser	synonymous	Exon 13 of 15	ENSP00000406191.2
	TRPV4	ENST00000536838.1	TSL:1	c.2202G>C	p.Ser734Ser	synonymous	Exon 14 of 16	ENSP00000444336.1

Frequencies

GnomAD3 genomes AF: 0.000506 AC: 77 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.000720

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: 0.000750

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000451 AC: 113 AN: 250770 AF XY: 0.000449

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000866

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000491 AC: 717 AN: 1461638 Hom.: 0 Cov.: 31 AF XY: 0.000501 AC XY: 364 AN XY: 727138

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000291 AC: 13 AN: 44722

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53184

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.000615 AC: 684 AN: 1111994

Other (OTH) AF: 0.000166 AC: 10 AN: 60396

GnomAD4 genome AF: 0.000506 AC: 77 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.000551 AC XY: 41 AN XY: 74466

African (AFR) AF: 0.0000962 AC: 4 AN: 41568

American (AMR) AF: 0.000719 AC: 11 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000629 Hom.: 0

Bravo AF: 0.000540

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.000948

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	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	-0.88
CADD	Benign	0.35
DANN	Benign	0.37
PhyloP100		-11
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs138986228; hg19: chr12-110224547;