4-121879818-T-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.2684A>G(p.Lys895Arg) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPC3 NM_001130698.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.11

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 where missense usually causes diseases, TRPC3
• BP4: Computational evidence support a benign effect (MetaRNN=0.24432808).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPC3	NM_001130698.2	c.2684A>G	p.Lys895Arg	missense_variant	12/12	ENST00000379645.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPC3	ENST00000379645.8	c.2684A>G	p.Lys895Arg	missense_variant	12/12	1	NM_001130698.2	P4
TRPC3	ENST00000264811.9	c.2465A>G	p.Lys822Arg	missense_variant	11/11	1		A2
TRPC3	ENST00000513531.1	c.2300A>G	p.Lys767Arg	missense_variant	10/10	1
TRPC3	ENST00000506449.1	c.*1692A>G		3_prime_UTR_variant, NMD_transcript_variant	12/12	1

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

Jun 09, 2022

The c.2684A>G (p.K895R) alteration is located in exon 12 (coding exon 12) of the TRPC3 gene. This alteration results from a A to G substitution at nucleotide position 2684, causing the lysine (K) at amino acid position 895 to be replaced by an arginine (R). 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	0.042	T
BayesDel_noAF	Benign	-0.18
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-0.30	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.88	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.35	T;T;T
Sift4G	Benign	0.61	T;T;T
Vest4		0.42
MVP		0.79
MPC		0.65
ClinPred		0.78	D
GERP RS		6.2
gMVP		0.63

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: chr4-122800973;