3-142736460-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001251845.2(TRPC1):c.254G>A(p.Arg85Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TRPC1 NM_001251845.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.55

Genes affected

TRPC1 (HGNC:12333): (transient receptor potential cation channel subfamily C member 1) 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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TRPC1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPC1	NM_001251845.2	c.254G>A	p.Arg85Lys	missense_variant	2/13	ENST00000476941.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPC1	ENST00000476941.6	c.254G>A	p.Arg85Lys	missense_variant	2/13	1	NM_001251845.2	P1
TRPC1	ENST00000273482.10	c.254G>A	p.Arg85Lys	missense_variant	2/12	1
TRPC1	ENST00000698238.1	c.563G>A	p.Arg188Lys	missense_variant	2/13
TRPC1	ENST00000460401.1	c.167+11729G>A		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460616 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726656

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

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

Jan 24, 2024

The c.254G>A (p.R85K) alteration is located in exon 2 (coding exon 2) of the TRPC1 gene. This alteration results from a G to A substitution at nucleotide position 254, causing the arginine (R) at amino acid position 85 to be replaced by a lysine (K). 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
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;.;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;.;D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.6	L;L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.8	D;D;.
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.014	D;D;D
Polyphen		0.92	P;D;D
Vest4		0.87
MutPred		0.78		Gain of ubiquitination at R85 (P = 0.0797);Gain of ubiquitination at R85 (P = 0.0797);Gain of ubiquitination at R85 (P = 0.0797);
MVP		0.63
MPC		0.61
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.82
gMVP		0.84

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

LitVar

Other links and lift over

dbSNP: rs750429181; hg19: chr3-142455302;