Variant chr13-37637265-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_016179.4(TRPC4):c.2572G>C(p.Glu858Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E858G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

TRPC4
NM_016179.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.91

Variant links:

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]

TRPC4 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13063785).

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPC4	NM_016179.4 linkuse as main transcript	c.2572G>C	p.Glu858Gln	missense_variant	11/11	ENST00000379705.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPC4	ENST00000379705.8 linkuse as main transcript	c.2572G>C	p.Glu858Gln	missense_variant	11/11	1	NM_016179.4	P4	Q9UBN4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250078

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135248

show subpopulations

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:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461632

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727120

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000301

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2024

The c.2587G>C (p.E863Q) alteration is located in exon 11 (coding exon 10) of the TRPC4 gene. This alteration results from a G to C substitution at nucleotide position 2587, causing the glutamic acid (E) at amino acid position 863 to be replaced by a glutamine (Q). 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

0.091

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;.;.;.

Eigen

Benign

0.025

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.79

T;T;T;.

M_CAP

Benign

0.015

MetaRNN

Benign

0.13

T;T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

0.69

N;.;.;.

MutationTaster

Benign

0.91

D;D;D;D;D;D;D;D;D

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.75

N;N;.;N

REVEL

Benign

0.093

Sift

Uncertain

0.011

D;D;.;D

Sift4G

Benign

0.25

T;T;T;T

Polyphen

0.72

P;P;B;P

Vest4

0.10

MutPred

0.26

Gain of MoRF binding (P = 0.0286);.;.;.;

MVP

0.53

ClinPred

0.17

GERP RS

4.7

BranchPoint Hunter

1.0

Varity_R

0.10

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over