4-121932961-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001130698.2(TRPC3):c.297C>G(p.Ala99=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 1,613,080 control chromosomes in the GnomAD database, including 9,148 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.075 (561 hom., cov: 33)
  • Exomes 𝑓: 0.10 (8587 hom.)
• Consequence: TRPC3 NM_001130698.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.829

Genes affected

TRPC3 (HGNC:12335): (transient receptor potential cation channel subfamily C member 3) The protein encoded by this gene is a membrane protein that can form a non-selective channel permeable to calcium and other cations. The encoded protein appears to be induced to form channels by a receptor tyrosine kinase-activated phosphatidylinositol second messenger system and also by depletion of intracellular calcium stores. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 4-121932961-G-C is Benign according to our data. Variant chr4-121932961-G-C is described in ClinVar as [Benign]. Clinvar id is 2135328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.829 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPC3	NM_001130698.2	c.297C>G	p.Ala99=	synonymous_variant	2/12	ENST00000379645.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPC3	ENST00000379645.8	c.297C>G	p.Ala99=	synonymous_variant	2/12	1	NM_001130698.2	P4

Frequencies

GnomAD3 genomes AF: 0.0751 AC: 11429 AN: 152200 Hom.: 559 Cov.: 33

Gnomad AFR AF: 0.0208

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0653

Gnomad ASJ AF: 0.0478

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0743

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.0802

GnomAD3 exomes AF: 0.0816 AC: 20279 AN: 248520 Hom.: 1026 AF XY: 0.0851 AC XY: 11475 AN XY: 134876

Gnomad AFR exome AF: 0.0159

Gnomad AMR exome AF: 0.0539

Gnomad ASJ exome AF: 0.0504

Gnomad EAS exome AF: 0.000276

Gnomad SAS exome AF: 0.0783

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.110

Gnomad OTH exome AF: 0.0988

GnomAD4 exome AF: 0.104 AC: 152173 AN: 1460762 Hom.: 8587 Cov.: 32 AF XY: 0.103 AC XY: 75144 AN XY: 726584

Gnomad4 AFR exome AF: 0.0172

Gnomad4 AMR exome AF: 0.0564

Gnomad4 ASJ exome AF: 0.0476

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0772

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.116

Gnomad4 OTH exome AF: 0.0939

GnomAD4 genome AF: 0.0751 AC: 11436 AN: 152318 Hom.: 561 Cov.: 33 AF XY: 0.0752 AC XY: 5604 AN XY: 74472

Gnomad4 AFR AF: 0.0209

Gnomad4 AMR AF: 0.0652

Gnomad4 ASJ AF: 0.0478

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0749

Gnomad4 FIN AF: 0.114

Gnomad4 NFE AF: 0.111

Gnomad4 OTH AF: 0.0794

Alfa AF: 0.0794 Hom.: 189

Bravo AF: 0.0685

Asia WGS AF: 0.0280 AC: 98 AN: 3478

EpiCase AF: 0.107

EpiControl AF: 0.114

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TRPC3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 20, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	8.4
Dann	Benign	0.81

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

LitVar

Other links and lift over

dbSNP: rs13121031; hg19: chr4-122854116;