13-37637342-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_016179.4(TRPC4):c.2495A>G(p.Lys832Arg) 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 benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPC4 NM_016179.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19

Genes affected

TRPC4 (HGNC:12336): (transient receptor potential cation channel subfamily C member 4) This gene encodes a member of the canonical subfamily of transient receptor potential cation channels. The encoded protein forms a non-selective calcium-permeable cation channel that is activated by Gq-coupled receptors and tyrosine kinases, and plays a role in multiple processes including endothelial permeability, vasodilation, neurotransmitter release and cell proliferation. Single nucleotide polymorphisms in this gene may be associated with generalized epilepsy with photosensitivity. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TRPC4
• BP4: Computational evidence support a benign effect (MetaRNN=0.25197202).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPC4	NM_016179.4	c.2495A>G	p.Lys832Arg	missense_variant	11/11	ENST00000379705.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPC4	ENST00000379705.8	c.2495A>G	p.Lys832Arg	missense_variant	11/11	1	NM_016179.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2024

The c.2510A>G (p.K837R) alteration is located in exon 11 (coding exon 10) of the TRPC4 gene. This alteration results from a A to G substitution at nucleotide position 2510, causing the lysine (K) at amino acid position 837 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	17
Dann	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T;T;T;.
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.81	L;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.33	N;N;.;N
REVEL	Benign	0.16
Sift	Benign	0.15	T;T;.;T
Sift4G	Benign	0.43	T;T;T;T
Polyphen		0.96	P;D;D;D
Vest4		0.074
MutPred		0.28		Loss of ubiquitination at K832 (P = 0.0107);.;.;.;
MVP		0.58
ClinPred		0.48	T
GERP RS		5.9
Varity_R		0.032
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-38211479;