3-142792828-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_001251845.2(TRPC1):c.1442A>G(p.His481Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000287 in 1,428,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: TRPC1 NM_001251845.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.82

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 Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TRPC1
• BP4: Computational evidence support a benign effect (MetaRNN=0.17138767).
• BS2: High AC in GnomAdExome at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPC1	NM_001251845.2	c.1442A>G	p.His481Arg	missense_variant	9/13	ENST00000476941.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPC1	ENST00000476941.6	c.1442A>G	p.His481Arg	missense_variant	9/13	1	NM_001251845.2	P1
TRPC1	ENST00000273482.10	c.1340A>G	p.His447Arg	missense_variant	8/12	1
TRPC1	ENST00000698238.1	c.1751A>G	p.His584Arg	missense_variant	9/13

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000312 AC: 7 AN: 224662 Hom.: 0 AF XY: 0.0000246 AC XY: 3 AN XY: 121916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000700

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000478

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000287 AC: 41 AN: 1428978 Hom.: 0 Cov.: 30 AF XY: 0.0000267 AC XY: 19 AN XY: 710604

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000767

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: 0.0000328

Gnomad4 OTH exome AF: 0.0000340

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000412 AC: 5

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 26, 2022

The c.1340A>G (p.H447R) alteration is located in exon 8 (coding exon 8) of the TRPC1 gene. This alteration results from a A to G substitution at nucleotide position 1340, causing the histidine (H) at amino acid position 447 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
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.22
Cadd	Uncertain	23
Dann	Benign	0.93
DEOGEN2	Uncertain	0.47	T;.;.
Eigen	Benign	-0.093
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;.;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.090	N;.;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.19	N;N;.
REVEL	Benign	0.21
Sift	Benign	0.45	T;T;.
Sift4G	Benign	0.85	T;T;T
Polyphen		0.042	B;B;B
Vest4		0.21
MutPred		0.58		Gain of MoRF binding (P = 0.0816);.;.;
MVP		0.71
MPC		1.3
ClinPred		0.11	T
GERP RS		5.2
Varity_R		0.17
gMVP		0.50

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: rs765355502; hg19: chr3-142511670;