rs41278087

Variant names:

• chr4-121879832-T-C
• rs41278087
• NM_001130698.2:c.2670A>G
• TRPC3 p.Glu890Glu

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001130698.2(TRPC3):​c.2670A>G​(p.Glu890Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0288 in 1,607,222 control chromosomes in the GnomAD database, including 868 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.022 (74 hom., cov: 32)
  • Exomes 𝑓: 0.030 (794 hom.)
• Consequence: TRPC3 NM_001130698.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.24
• Publications: 4 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: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 4-121879832-T-C is Benign according to our data. Variant chr4-121879832-T-C is described in ClinVar as Benign. ClinVar VariationId is 2003811.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.24 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0221 (3360/152260) while in subpopulation NFE AF = 0.0319 (2170/67998). AF 95% confidence interval is 0.0308. There are 74 homozygotes in GnomAd4. There are 1672 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3360 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001130698.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPC3	NM_001130698.2	MANE Select	c.2670A>G	p.Glu890Glu	synonymous	Exon 12 of 12	NP_001124170.1	Q13507-2
	TRPC3	NM_001366479.2		c.2586A>G	p.Glu862Glu	synonymous	Exon 11 of 11	NP_001353408.1
	TRPC3	NM_003305.2		c.2451A>G	p.Glu817Glu	synonymous	Exon 11 of 11	NP_003296.1	Q13507-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPC3	ENST00000379645.8	TSL:1 MANE Select	c.2670A>G	p.Glu890Glu	synonymous	Exon 12 of 12	ENSP00000368966.3	Q13507-2
	TRPC3	ENST00000264811.9	TSL:1	c.2451A>G	p.Glu817Glu	synonymous	Exon 11 of 11	ENSP00000264811.5	Q13507-3
	TRPC3	ENST00000513531.1	TSL:1	c.2286A>G	p.Glu762Glu	synonymous	Exon 10 of 10	ENSP00000426899.1	J3QTB0

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3361 AN: 152142 Hom.: 74 Cov.: 32

Gnomad AFR AF: 0.00502

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.00785

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.0624

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0319

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.0219 AC: 5320 AN: 242886 AF XY: 0.0217

Gnomad AFR exome AF: 0.00446

Gnomad AMR exome AF: 0.00375

Gnomad ASJ exome AF: 0.00774

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0595

Gnomad NFE exome AF: 0.0317

Gnomad OTH exome AF: 0.0191

GnomAD4 exome AF: 0.0295 AC: 42945 AN: 1454962 Hom.: 794 Cov.: 30 AF XY: 0.0286 AC XY: 20664 AN XY: 723564

African (AFR) AF: 0.00426 AC: 141 AN: 33122

American (AMR) AF: 0.00426 AC: 184 AN: 43226

Ashkenazi Jewish (ASJ) AF: 0.00806 AC: 210 AN: 26054

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39218

South Asian (SAS) AF: 0.00500 AC: 421 AN: 84284

European-Finnish (FIN) AF: 0.0593 AC: 3162 AN: 53328

Middle Eastern (MID) AF: 0.00365 AC: 21 AN: 5750

European-Non Finnish (NFE) AF: 0.0338 AC: 37467 AN: 1109798

Other (OTH) AF: 0.0222 AC: 1338 AN: 60182

GnomAD4 genome AF: 0.0221 AC: 3360 AN: 152260 Hom.: 74 Cov.: 32 AF XY: 0.0225 AC XY: 1672 AN XY: 74462

African (AFR) AF: 0.00501 AC: 208 AN: 41552

American (AMR) AF: 0.00784 AC: 120 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00600 AC: 29 AN: 4830

European-Finnish (FIN) AF: 0.0624 AC: 662 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0319 AC: 2170 AN: 67998

Other (OTH) AF: 0.0104 AC: 22 AN: 2108

Alfa AF: 0.0267 Hom.: 52

Bravo AF: 0.0172

Asia WGS AF: 0.00202 AC: 8 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	4.5
DANN	Benign	0.55
PhyloP100		1.2
Mutation Taster		=96/4	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41278087;

hg19: chr4-122800987;