4-121882367-A-C

Position:

• chr4-121882367-A-C

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.2610T>G​(p.Asp870Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPC3 NM_001130698.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.90

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=0.26094496).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPC3	NM_001130698.2	c.2610T>G	p.Asp870Glu	missense_variant	11/12	ENST00000379645.8	NP_001124170.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPC3	ENST00000379645.8	c.2610T>G	p.Asp870Glu	missense_variant	11/12	1	NM_001130698.2	ENSP00000368966.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 09, 2024

The c.2610T>G (p.D870E) alteration is located in exon 11 (coding exon 11) of the TRPC3 gene. This alteration results from a T to G substitution at nucleotide position 2610, causing the aspartic acid (D) at amino acid position 870 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	20
DANN	Uncertain	0.98
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.26	T;T;T
MetaSVM	Benign	-0.59	T
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.5	N;D;D
REVEL	Uncertain	0.56
Sift	Benign	0.045	D;T;T
Sift4G	Benign	0.36	T;T;T
Vest4		0.47
MVP		0.45
MPC		0.99
ClinPred		0.87	D
GERP RS		3.4
gMVP		0.47

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-122803522;