chr13-37637211-C-A

Variant names:

• chr13-37637211-C-A
• rs751793234
• NM_016179.4:c.2626G>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_016179.4(TRPC4):​c.2626G>T​(p.Ala876Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A876P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: TRPC4 NM_016179.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.47

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.115799576).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPC4	NM_016179.4	c.2626G>T	p.Ala876Ser	missense_variant	Exon 11 of 11	ENST00000379705.8	NP_057263.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPC4	ENST00000379705.8	c.2626G>T	p.Ala876Ser	missense_variant	Exon 11 of 11	1	NM_016179.4	ENSP00000369027.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250898 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135608

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: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461634 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727116

Gnomad4 AFR exome AF: 0.00

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.: 32

Alfa AF: 0.0000254 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.;.;.;.;.;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;D;.;D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.81	L;.;.;.;.;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.030	N;N;.;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.20	T;T;.;T;T;T;D
Sift4G	Benign	0.52	T;T;T;T;T;T;T
Polyphen		0.031	B;B;P;B;B;D;D
Vest4		0.27
MVP		0.22
ClinPred		0.21	T
GERP RS		5.8
Varity_R		0.040
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs751793234; hg19: chr13-38211348; COSMIC: COSV59017336;