12-109792732-G-C

Position:

• chr12-109792732-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_021625.5(TRPV4):​c.1744C>G​(p.Leu582Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L582L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TRPV4 NM_021625.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.63

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity TRPV4_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) in NM_021625.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TRPV4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPV4	NM_021625.5	c.1744C>G	p.Leu582Val	missense_variant	11/16	ENST00000261740.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPV4	ENST00000261740.7	c.1744C>G	p.Leu582Val	missense_variant	11/16	1	NM_021625.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251286 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135854

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;D;.;.;.;.
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.8	M;M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D;D;D;D;D;D
Sift4G	Uncertain	0.024	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D
Vest4		0.79
MutPred		0.62		Gain of catalytic residue at L584 (P = 0);Gain of catalytic residue at L584 (P = 0);.;.;.;.;
MVP		0.93
MPC		2.1
ClinPred		0.92	D
GERP RS		1.6
Varity_R		0.59
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs35078611; hg19: chr12-110230537;