4-121902897-C-G

Position:

• chr4-121902897-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001130698.2(TRPC3):​c.2418G>C​(p.Arg806Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R806R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPC3 NM_001130698.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.635

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TRPC3. . Gene score misZ 3.8433 (greater than the threshold 3.09). Trascript score misZ 3.0976 (greater than threshold 3.09). GenCC has associacion of gene with spinocerebellar ataxia type 41.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24445814).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPC3	NM_001130698.2	c.2418G>C	p.Arg806Ser	missense_variant	9/12	ENST00000379645.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPC3	ENST00000379645.8	c.2418G>C	p.Arg806Ser	missense_variant	9/12	1	NM_001130698.2	P4
TRPC3	ENST00000264811.9	c.2199G>C	p.Arg733Ser	missense_variant	8/11	1		A2
TRPC3	ENST00000513531.1	c.2034G>C	p.Arg678Ser	missense_variant	7/10	1
TRPC3	ENST00000506449.1	c.*1426G>C		3_prime_UTR_variant, NMD_transcript_variant	9/12	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.093	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	17
DANN	Benign	0.92
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	0.0054	P;P;P
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.37	N;N;N
REVEL	Uncertain	0.37
Sift	Benign	0.85	T;T;T
Sift4G	Benign	0.83	T;T;T
Vest4		0.16
MVP		0.41
MPC		0.86
ClinPred		0.31	T
GERP RS		2.6
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs11732666; hg19: chr4-122824052;