rs200497189

Variant names:

• chr12-109803087-G-A
• rs200497189
• NM_021625.5:c.616C>T
• TRPV4 p.Arg206Cys

Your query was ambiguous. Multiple possible variants found:

• chr12-109803087-G-A
• chr12-109803087-G-C

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACGS-UK Somatic Oncogenicity v2025).

The NM_021625.5(TRPV4):c.616C>T (p.Arg206Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene TRPV4 is a known oncogene (CancerMine: 6 oncogene, 3 driver citations). The gene TRPV4 is a cancer driver gene (CancerMine: 6 oncogene, 3 driver citations). The variant allele was found at a cumulative frequency of 0.0000445 (AC=65) in the gnomAD database across 1,461,830 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000154. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R206H: Uncertain_significance (ClinVar VariationId 684495, 2 stars); p.R206L: Uncertain_significance (ClinVar VariationId 1320389, 2 stars) The variant has been observed in cBioPortal in 3 samples across 3 studies and 3 cancer types; somatic enrichment level: SUPPORTING_LOW (Observed in a small number of cBioPortal cases.). 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: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: TRPV4 NM_021625.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.00
• 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: 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

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
No applied criteria Uncheck "Show applied only" above to review all 20 criteria.

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

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TRPV4 NM_021625.5	MANE Select	c.616C>T p.Arg206Cys	missense	Exon 4 of 16	Prot: NP_067638.3
	TRPV4 NM_001177431.1		c.514C>T p.Arg172Cys	missense	Exon 4 of 16	Prot: NP_001170902.1 UniProt:
	TRPV4 NM_001177428.1		c.616C>T p.Arg206Cys	missense	Exon 3 of 14	Prot: NP_001170899.1 UniProt:

TRPV4 NM_021625.5

MANE Select

HGVSc / HGVSpc.616C>Tp.Arg206Cys

Exon rankExon 4 of 16

missense

Prot: NP_067638.3

TRPV4 NM_001177431.1

HGVSc / HGVSpc.514C>Tp.Arg172Cys

Exon rankExon 4 of 16

missense

Prot: NP_001170902.1UniProt: Q9HBA0-5

TRPV4 NM_001177428.1

HGVSc / HGVSpc.616C>Tp.Arg206Cys

Exon rankExon 3 of 14

missense

Prot: NP_001170899.1UniProt: Q9HBA0-4

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TRPV4 ENST00000261740.7	TSL:1MANE Select	c.616C>T p.Arg206Cys	missense	Exon 4 of 16	Prot: ENSP00000261740.2 UniProt:
	TRPV4 ENST00000418703.7	TSL:1	c.616C>T p.Arg206Cys	missense	Exon 3 of 15	Prot: ENSP00000406191.2 UniProt:
	TRPV4 ENST00000536838.1	TSL:1	c.514C>T p.Arg172Cys	missense	Exon 4 of 16	Prot: ENSP00000444336.1 UniProt:

TRPV4 ENST00000261740.7

TSL:1MANE Select

HGVSc / HGVSpc.616C>Tp.Arg206Cys

Exon rankExon 4 of 16

missense

Prot: ENSP00000261740.2UniProt: Q9HBA0-1

TRPV4 ENST00000418703.7

TSL:1

HGVSc / HGVSpc.616C>Tp.Arg206Cys

Exon rankExon 3 of 15

missense

Prot: ENSP00000406191.2UniProt: Q9HBA0-1

TRPV4 ENST00000536838.1

TSL:1

HGVSc / HGVSpc.514C>Tp.Arg172Cys

Exon rankExon 4 of 16

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000263	AC:4	Hom:0	AN:152194	Cov:32
GnomAD2 exomes	AF: 0.0000716	AC:18	Hom:	AN:251228	Cov:
GnomAD4 exome	AF: 0.0000445	AC:65	Hom:0	AN:1461830	Cov:34
GnomAD4 genome Warning	AF: 0.0000263	AC:4	Hom:0	AN:152312	Cov:32
TOPMed (Bravo)	AF: 0.0000189	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000316	AC:7	Hom:0	AN:221622	Cov:
Local & regional cohorts 3 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000427	AC:1	Hom:0	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0000985	AC:	Hom:	AN:	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000223	AC:2	Hom:0	AN:8960	Cov:

Showing 9 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00 *	0	1490	0.000139 *	1	7190
BipEx(Bipolar disorder (including schizoaffective))	0.0000704	2	28420	0.0000347	1	28844
Epi25(Epilepsy)	0.0000477	2	41958	0.0000897	6	66888
SCHEMA(Schizophrenia)	0.0000449	5	111306	0.0000709	13	183414

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Charcot-Marie-Tooth disease axonal type 2C (1)
-	-	1	Inborn genetic diseases (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	20
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	0.13
Eigen_PC	Benign	0.080
FATHMM_MKL	Benign	0.46	N
FuncVEP CTI	Benign	0.015
GPN-Star LLR	N/A	-5.2
GPN-Star score	N/A	5.2
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	0.51	D
Mutation Taster	N/A	54/46	polymorphism
MutationAssessor	Benign	1.8	L
PhyloP100	Benign	2.0
popEVE	Benign	-3.3
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.037	D
Varity_R	N/A	0.22
VESM-3B	Benign	-8.7

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

Other links and lift over

dbSNP: rs200497189;

hg19: chr12-110240892;

COSMIC: COSV99924972;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar