4-121899620-G-C

Variant names:

• chr4-121899620-G-C
• rs138232580
• NM_001130698.2:c.2539C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001130698.2(TRPC3):​c.2539C>G​(p.Arg847Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,706 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R847C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TRPC3 NM_001130698.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.36
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2539C>G	p.Arg847Gly	missense	Exon 10 of 12	NP_001124170.1	Q13507-2
	TRPC3	NM_003305.2		c.2320C>G	p.Arg774Gly	missense	Exon 9 of 11	NP_003296.1	Q13507-3
	TRPC3	NM_001366479.2		c.2463+3232C>G		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.2539C>G	p.Arg847Gly	missense	Exon 10 of 12	ENSP00000368966.3	Q13507-2
	TRPC3	ENST00000264811.9	TSL:1	c.2320C>G	p.Arg774Gly	missense	Exon 9 of 11	ENSP00000264811.5	Q13507-3
	TRPC3	ENST00000513531.1	TSL:1	c.2155C>G	p.Arg719Gly	missense	Exon 8 of 10	ENSP00000426899.1	J3QTB0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460706 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726706

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.00 AC: 0 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111204

Other (OTH) AF: 0.00 AC: 0 AN: 60326

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	0.17	D
PhyloP100		6.4
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.64
Sift	Benign	0.089	T
Sift4G	Benign	0.080	T
Vest4		0.79
MVP		0.76
MPC		1.2
ClinPred		0.98	D
GERP RS		5.6
gMVP		0.75
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs138232580; hg19: chr4-122820775;