Genetic Variant TRPV4:p.Arg206Cys (chr12-109803085-GCG-ACA) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_021625.5(TRPV4):c.616_618delCGCinsTGT (p.Arg206Cys) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R206C: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 520860); p.R206H: Uncertain_significance (ClinVar VariationId 684495, 2 stars); p.R206L: Uncertain_significance (ClinVar VariationId 1320389, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Nevi and Melanomas; it is also listed as a COSMIC curated somatic variant.

Frequency

Genomes: not found (cov: 32)

Consequence

TRPV4
NM_021625.5 missense

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.00

Publications

0 publications found

Variant links:

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, Orphanet
neuromuscular disease
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, ClinGen
spondylometaphyseal dysplasia, Kozlowski type
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
TRPV4-related bone disorder
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, PanelApp Australia, 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
scapuloperoneal spinal muscular atrophy, autosomal dominant
Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
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

TRPV4 links:

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new If you want to explore the variant's impact on the transcript NM_021625.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Show applied only (1)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_021625.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
TRPV4 NM_021625.5	MANE Select	c.616_618delCGCinsTGT p.Arg206Cys	missense	N/A	Prot: NP_067638.3
TRPV4 NM_001177431.1		c.514_516delCGCinsTGT p.Arg172Cys	missense	N/A	Prot: NP_001170902.1 UniProt: Q9HBA0-5
TRPV4 NM_001177428.1		c.616_618delCGCinsTGT p.Arg206Cys	missense	N/A	Prot: NP_001170899.1 UniProt: Q9HBA0-4

TRPV4 NM_021625.5

MANE Select

HGVSc / HGVSpc.616_618delCGCinsTGTp.Arg206Cys

Exon rankN/A

missense

Prot: NP_067638.3

TRPV4 NM_001177431.1

HGVSc / HGVSpc.514_516delCGCinsTGTp.Arg172Cys

Exon rankN/A

missense

Prot: NP_001170902.1UniProt: Q9HBA0-5

TRPV4 NM_001177428.1

HGVSc / HGVSpc.616_618delCGCinsTGTp.Arg206Cys

Exon rankN/A

missense

Prot: NP_001170899.1UniProt: Q9HBA0-4

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
TRPV4 ENST00000261740.7	TSL:1MANE Select	c.616_618delCGCinsTGT p.Arg206Cys	missense	N/A	Prot: ENSP00000261740.2 UniProt: Q9HBA0-1
TRPV4 ENST00000418703.7	TSL:1	c.616_618delCGCinsTGT p.Arg206Cys	missense	N/A	Prot: ENSP00000406191.2 UniProt: Q9HBA0-1
TRPV4 ENST00000536838.1	TSL:1	c.514_516delCGCinsTGT p.Arg172Cys	missense	N/A	Prot: ENSP00000444336.1 UniProt: Q9HBA0-5

TRPV4 ENST00000261740.7

TSL:1MANE Select

HGVSc / HGVSpc.616_618delCGCinsTGTp.Arg206Cys

Exon rankN/A

missense

Prot: ENSP00000261740.2UniProt: Q9HBA0-1

TRPV4 ENST00000418703.7

TSL:1

HGVSc / HGVSpc.616_618delCGCinsTGTp.Arg206Cys

Exon rankN/A

missense

Prot: ENSP00000406191.2UniProt: Q9HBA0-1

TRPV4 ENST00000536838.1

TSL:1

HGVSc / HGVSpc.514_516delCGCinsTGTp.Arg172Cys

Exon rankN/A

missense

Prot: ENSP00000444336.1UniProt: Q9HBA0-5

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Benign	2.0

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence