rs139940353

Variant names:

• chr4-121899690-G-A
• rs139940353
• NM_001130698.2:c.2469C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001130698.2(TRPC3):​c.2469C>T​(p.Asn823Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,610,738 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: TRPC3 NM_001130698.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.07
• Publications: 1 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 4-121899690-G-A is Benign according to our data. Variant chr4-121899690-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 738682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.07 with no splicing effect.
• BS2: High AC in GnomAd4 at 13 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.2469C>T	p.Asn823Asn	synonymous	Exon 10 of 12	NP_001124170.1	Q13507-2
	TRPC3	NM_003305.2		c.2250C>T	p.Asn750Asn	synonymous	Exon 9 of 11	NP_003296.1	Q13507-3
	TRPC3	NM_001366479.2		c.2463+3162C>T		intron	N/A	NP_001353408.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPC3	ENST00000379645.8	TSL:1 MANE Select	c.2469C>T	p.Asn823Asn	synonymous	Exon 10 of 12	ENSP00000368966.3	Q13507-2
	TRPC3	ENST00000264811.9	TSL:1	c.2250C>T	p.Asn750Asn	synonymous	Exon 9 of 11	ENSP00000264811.5	Q13507-3
	TRPC3	ENST00000513531.1	TSL:1	c.2085C>T	p.Asn695Asn	synonymous	Exon 8 of 10	ENSP00000426899.1	J3QTB0

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000112 AC: 28 AN: 249176 AF XY: 0.000111

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00130

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000889

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000147 AC: 214 AN: 1458620 Hom.: 1 Cov.: 29 AF XY: 0.000147 AC XY: 107 AN XY: 725808

African (AFR) AF: 0.0000899 AC: 3 AN: 33380

American (AMR) AF: 0.000135 AC: 6 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.000767 AC: 20 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85990

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53298

Middle Eastern (MID) AF: 0.00504 AC: 29 AN: 5754

European-Non Finnish (NFE) AF: 0.000121 AC: 134 AN: 1109742

Other (OTH) AF: 0.000349 AC: 21 AN: 60258

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74314

African (AFR) AF: 0.0000241 AC: 1 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68000

Other (OTH) AF: 0.000958 AC: 2 AN: 2088

Alfa AF: 0.000127 Hom.: 0

Bravo AF: 0.000147

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	TRPC3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.9
DANN	Benign	0.63
PhyloP100		3.1
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs139940353; hg19: chr4-122820845;