rs779371027

Variant names:

• chr12-109808460-G-A
• rs779371027
• NM_021625.5:c.395C>T
• TRPV4 p.Pro132Leu

Your query was ambiguous. Multiple possible variants found:

• chr12-109808460-G-A
• chr12-109808460-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 (ACMG Germline Pathogenicity v2019).

The NM_021625.5(TRPV4):c.395C>T (p.Pro132Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000292 (AC=47) in the gnomAD database across 1,612,220 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000121. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.P132= (synonymous): Likely_benign (ClinVar VariationId 917309, 2 stars); p.P132= (synonymous): Benign/Likely_benign (ClinVar VariationId 241388, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: TRPV4 NM_021625.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.71
• 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 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
No applied criteria Uncheck "Show applied only" above to review all 28 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.395C>T p.Pro132Leu	missense	Exon 3 of 16	Prot: NP_067638.3
	TRPV4 NM_001177431.1		c.293C>T p.Pro98Leu	missense	Exon 3 of 16	Prot: NP_001170902.1 UniProt:
	TRPV4 NM_001177428.1		c.395C>T p.Pro132Leu	missense	Exon 2 of 14	Prot: NP_001170899.1 UniProt:

TRPV4 NM_021625.5

MANE Select

HGVSc / HGVSpc.395C>Tp.Pro132Leu

Exon rankExon 3 of 16

missense

Prot: NP_067638.3

TRPV4 NM_001177431.1

HGVSc / HGVSpc.293C>Tp.Pro98Leu

Exon rankExon 3 of 16

missense

Prot: NP_001170902.1UniProt: Q9HBA0-5

TRPV4 NM_001177428.1

HGVSc / HGVSpc.395C>Tp.Pro132Leu

Exon rankExon 2 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.395C>T p.Pro132Leu	missense	Exon 3 of 16	Prot: ENSP00000261740.2 UniProt:
	TRPV4 ENST00000418703.7	TSL:1	c.395C>T p.Pro132Leu	missense	Exon 2 of 15	Prot: ENSP00000406191.2 UniProt:
	TRPV4 ENST00000536838.1	TSL:1	c.293C>T p.Pro98Leu	missense	Exon 3 of 16	Prot: ENSP00000444336.1 UniProt:

TRPV4 ENST00000261740.7

TSL:1MANE Select

HGVSc / HGVSpc.395C>Tp.Pro132Leu

Exon rankExon 3 of 16

missense

Prot: ENSP00000261740.2UniProt: Q9HBA0-1

TRPV4 ENST00000418703.7

TSL:1

HGVSc / HGVSpc.395C>Tp.Pro132Leu

Exon rankExon 2 of 15

missense

Prot: ENSP00000406191.2UniProt: Q9HBA0-1

TRPV4 ENST00000536838.1

TSL:1

HGVSc / HGVSpc.293C>Tp.Pro98Leu

Exon rankExon 3 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: 0.0000131	AC:2	Hom:0	AN:152120	Cov:32
GnomAD2 exomes	AF: 0.0000403	AC:10	Hom:	AN:248274	Cov:
GnomAD4 exome	AF: 0.0000308	AC:45	Hom:0	AN:1460100	Cov:32
GnomAD4 genome	AF: 0.0000131	AC:2	Hom:0	AN:152120	Cov:32
TOPMed (Bravo)	AF: 0.0000340	AC:9	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000785	AC:3	Hom:0	AN:38216	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.00	0	28420	0.0000347	1	28844
Epi25(Epilepsy)	0.0000477	2	41958	0.0000598	4	66880
SCHEMA(Schizophrenia)	0.00000980	1	102002	0.0000274	5	182754

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	21
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.70	D
FuncVEP CTI	Benign	0.0022
GPN-Star LLR	N/A	-5.0
GPN-Star score	N/A	5.0
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.56	T
Mutation Taster	N/A	92/8	polymorphism
MutationAssessor	Benign	1.4	L
PhyloP100	Benign	1.7
popEVE	Benign	-3.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.70	N
REVEL	Uncertain	0.30
Sift	Benign	0.12	T
Sift4G	Benign	0.31	T
Varity_R	N/A	0.054
VESM-3B	Benign	-4.2

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: rs779371027;

hg19: chr12-110246265;

COSMIC: COSV99924717;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar