3-142724665-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001251845.2(TRPC1):c.106G>A(p.Asp36Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,224 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TRPC1 NM_001251845.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.17

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, TRPC1
• BP4: Computational evidence support a benign effect (MetaRNN=0.26536968).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPC1	NM_001251845.2	c.106G>A	p.Asp36Asn	missense_variant	1/13	ENST00000476941.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPC1	ENST00000476941.6	c.106G>A	p.Asp36Asn	missense_variant	1/13	1	NM_001251845.2	P1
TRPC1	ENST00000273482.10	c.106G>A	p.Asp36Asn	missense_variant	1/12	1
TRPC1	ENST00000698238.1	c.415G>A	p.Asp139Asn	missense_variant	1/13
TRPC1	ENST00000460401.1	c.103G>A	p.Asp35Asn	missense_variant, NMD_transcript_variant	1/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248944 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134724

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460224 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726432

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

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 26, 2022

The c.106G>A (p.D36N) alteration is located in exon 1 (coding exon 1) of the TRPC1 gene. This alteration results from a G to A substitution at nucleotide position 106, causing the aspartic acid (D) at amino acid position 36 to be replaced by an asparagine (N). 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	0.26
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.43
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.17	T;.;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	D;.;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.81	L;L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.88	N;N;.
REVEL	Uncertain	0.29
Sift	Benign	0.060	T;T;.
Sift4G	Benign	0.41	T;T;T
Polyphen		0.99	D;D;D
Vest4		0.28
MutPred		0.25		Gain of helix (P = 0.0164);Gain of helix (P = 0.0164);Gain of helix (P = 0.0164);
MVP		0.66
MPC		0.60
ClinPred		0.85	D
GERP RS		2.9
Varity_R		0.095
gMVP		0.44

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: rs777998269; hg19: chr3-142443507;