NM_021625.5:c.616C>G

Variant names:

• chr12-109803087-G-C
• rs200497189
• NM_021625.5:c.616C>G
• TRPV4 p.Arg206Gly

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

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

The NM_021625.5(TRPV4):c.616C>G (p.Arg206Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,830 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000000899. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. 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)

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TRPV4 NM_021625.5 missense
• Clinical Significance: Not reported in ClinVar
• 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000899 — very rare for AD/XL gene (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

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TRPV4 NM_021625.5	MANE Select	c.616C>G p.Arg206Gly	missense	Exon 4 of 16	Prot: NP_067638.3
	TRPV4 NM_001177431.1		c.514C>G p.Arg172Gly	missense	Exon 4 of 16	Prot: NP_001170902.1 UniProt:
	TRPV4 NM_001177428.1		c.616C>G p.Arg206Gly	missense	Exon 3 of 14	Prot: NP_001170899.1 UniProt:

TRPV4 NM_021625.5

MANE Select

HGVSc / HGVSpc.616C>Gp.Arg206Gly

Exon rankExon 4 of 16

missense

Prot: NP_067638.3

TRPV4 NM_001177431.1

HGVSc / HGVSpc.514C>Gp.Arg172Gly

Exon rankExon 4 of 16

missense

Prot: NP_001170902.1UniProt: Q9HBA0-5

TRPV4 NM_001177428.1

HGVSc / HGVSpc.616C>Gp.Arg206Gly

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>G p.Arg206Gly	missense	Exon 4 of 16	Prot: ENSP00000261740.2 UniProt:
	TRPV4 ENST00000418703.7	TSL:1	c.616C>G p.Arg206Gly	missense	Exon 3 of 15	Prot: ENSP00000406191.2 UniProt:
	TRPV4 ENST00000536838.1	TSL:1	c.514C>G p.Arg172Gly	missense	Exon 4 of 16	Prot: ENSP00000444336.1 UniProt:

TRPV4 ENST00000261740.7

TSL:1MANE Select

HGVSc / HGVSpc.616C>Gp.Arg206Gly

Exon rankExon 4 of 16

missense

Prot: ENSP00000261740.2UniProt: Q9HBA0-1

TRPV4 ENST00000418703.7

TSL:1

HGVSc / HGVSpc.616C>Gp.Arg206Gly

Exon rankExon 3 of 15

missense

Prot: ENSP00000406191.2UniProt: Q9HBA0-1

TRPV4 ENST00000536838.1

TSL:1

HGVSc / HGVSpc.514C>Gp.Arg172Gly

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 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461830	Cov:34
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	21
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.52	D
FuncVEP CTI	Pathogenic	0.57
GPN-Star LLR	N/A	-7.7
GPN-Star score	N/A	7.7
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.39	T
Mutation Taster	N/A	53/47	polymorphism
MutationAssessor	Benign	1.8	L
PhyloP100	Benign	2.0
popEVE	Benign	-3.2
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.49
Sift	Benign	0.070	T
Sift4G	Benign	0.25	T
Varity_R	N/A	0.37
VESM-3B	Benign	-9.0

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;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar