4-121932961-G-C

Variant names:

• chr4-121932961-G-C
• rs13121031
• NM_001130698.2:c.297C>G

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The ENST00000379645.8(TRPC3):​c.297C>G​(p.Ala99Ala) 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 ENST00000379645.8 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.829
• Publications: 13 publications found

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]

TRPC3 Gene-Disease associations (from GenCC):

• spinocerebellar ataxia type 41

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -15 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 VariationId is 2135328.Status of the report is criteria_provided_single_submitter, 1 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000379645.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPC3	NM_001130698.2	MANE Select	c.297C>G	p.Ala99Ala	synonymous	Exon 2 of 12	NP_001124170.1
	TRPC3	NM_001366479.2		c.297C>G	p.Ala99Ala	synonymous	Exon 2 of 11	NP_001353408.1
	TRPC3	NM_003305.2		c.78C>G	p.Ala26Ala	synonymous	Exon 1 of 11	NP_003296.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPC3	ENST00000379645.8	TSL:1 MANE Select	c.297C>G	p.Ala99Ala	synonymous	Exon 2 of 12	ENSP00000368966.3
	TRPC3	ENST00000264811.9	TSL:1	c.78C>G	p.Ala26Ala	synonymous	Exon 1 of 11	ENSP00000264811.5
	TRPC3	ENST00000513531.1	TSL:1	c.78C>G	p.Ala26Ala	synonymous	Exon 1 of 10	ENSP00000426899.1

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

GnomAD2 exomes AF: 0.0816 AC: 20279 AN: 248520 AF XY: 0.0851

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 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

African (AFR) AF: 0.0172 AC: 574 AN: 33462

American (AMR) AF: 0.0564 AC: 2518 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.0476 AC: 1243 AN: 26112

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39680

South Asian (SAS) AF: 0.0772 AC: 6655 AN: 86156

European-Finnish (FIN) AF: 0.113 AC: 5997 AN: 53118

Middle Eastern (MID) AF: 0.114 AC: 657 AN: 5762

European-Non Finnish (NFE) AF: 0.116 AC: 128857 AN: 1111468

Other (OTH) AF: 0.0939 AC: 5667 AN: 60364

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

African (AFR) AF: 0.0209 AC: 867 AN: 41582

American (AMR) AF: 0.0652 AC: 998 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0478 AC: 166 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.0749 AC: 362 AN: 4830

European-Finnish (FIN) AF: 0.114 AC: 1212 AN: 10608

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7583 AN: 68024

Other (OTH) AF: 0.0794 AC: 168 AN: 2116

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	TRPC3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	8.4
DANN	Benign	0.81
PhyloP100		-0.83
PromoterAI		-0.039	Neutral
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13121031; hg19: chr4-122854116;