rs10850750

Variant names:

• chr12-109793912-C-G
• rs10850750
• NM_021625.5:c.1584+18G>C

Your query was ambiguous. Multiple possible variants found:

• chr12-109793912-C-G
• chr12-109793912-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021625.5(TRPV4):​c.1584+18G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,434,736 control chromosomes in the GnomAD database, including 50,741 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3667 hom., cov: 28)
  • Exomes 𝑓: 0.26 (50741 hom.)
  • Failed GnomAD Quality Control
• Consequence: TRPV4 NM_021625.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.705
• 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
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 12-109793912-C-G is Benign according to our data. Variant chr12-109793912-C-G is described in ClinVar as Benign. ClinVar VariationId is 261414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.273 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPV4	NM_021625.5	MANE Select	c.1584+18G>C		intron	N/A	NP_067638.3
	TRPV4	NM_001177431.1		c.1482+18G>C		intron	N/A	NP_001170902.1
	TRPV4	NM_001177428.1		c.1443+18G>C		intron	N/A	NP_001170899.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPV4	ENST00000261740.7	TSL:1 MANE Select	c.1584+18G>C		intron	N/A	ENSP00000261740.2
	TRPV4	ENST00000418703.7	TSL:1	c.1584+18G>C		intron	N/A	ENSP00000406191.2
	TRPV4	ENST00000536838.1	TSL:1	c.1482+18G>C		intron	N/A	ENSP00000444336.1

Frequencies

GnomAD3 genomes AF: 0.200 AC: 29745 AN: 148466 Hom.: 3664 Cov.: 28

Gnomad AFR AF: 0.0561

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.297

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.258

Gnomad FIN AF: 0.253

Gnomad MID AF: 0.255

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.216

GnomAD2 exomes AF: 0.226 AC: 51293 AN: 226850 AF XY: 0.233

Gnomad AFR exome AF: 0.0467

Gnomad AMR exome AF: 0.202

Gnomad ASJ exome AF: 0.288

Gnomad EAS exome AF: 0.120

Gnomad FIN exome AF: 0.255

Gnomad NFE exome AF: 0.254

Gnomad OTH exome AF: 0.246

GnomAD4 exome AF: 0.261 AC: 374489 AN: 1434736 Hom.: 50741 Cov.: 31 AF XY: 0.262 AC XY: 186592 AN XY: 712480

African (AFR) AF: 0.0500 AC: 1662 AN: 33234

American (AMR) AF: 0.205 AC: 8562 AN: 41718

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 7394 AN: 25648

East Asian (EAS) AF: 0.126 AC: 4922 AN: 39152

South Asian (SAS) AF: 0.274 AC: 22714 AN: 82970

European-Finnish (FIN) AF: 0.257 AC: 13364 AN: 51960

Middle Eastern (MID) AF: 0.268 AC: 1489 AN: 5550

European-Non Finnish (NFE) AF: 0.274 AC: 299523 AN: 1094946

Other (OTH) AF: 0.249 AC: 14859 AN: 59558

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.200 AC: 29747 AN: 148584 Hom.: 3667 Cov.: 28 AF XY: 0.200 AC XY: 14442 AN XY: 72338

African (AFR) AF: 0.0560 AC: 2277 AN: 40652

American (AMR) AF: 0.221 AC: 3281 AN: 14838

Ashkenazi Jewish (ASJ) AF: 0.297 AC: 1023 AN: 3444

East Asian (EAS) AF: 0.123 AC: 610 AN: 4956

South Asian (SAS) AF: 0.259 AC: 1197 AN: 4630

European-Finnish (FIN) AF: 0.253 AC: 2535 AN: 10026

Middle Eastern (MID) AF: 0.255 AC: 73 AN: 286

European-Non Finnish (NFE) AF: 0.270 AC: 18017 AN: 66806

Other (OTH) AF: 0.216 AC: 446 AN: 2068

Alfa AF: 0.0496 Hom.: 166

Bravo AF: 0.192

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease axonal type 2C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.0020
DANN	Benign	0.44
PhyloP100		-0.70
Mutation Taster		=100/0	polymorphism (auto)

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: rs10850750; hg19: chr12-110231717; COSMIC: COSV55682442;