3-142724646-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001251845.2(TRPC1):c.87C>A(p.Asn29Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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)
• Consequence: TRPC1 NM_001251845.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.54

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 1 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=0.18953928).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPC1	NM_001251845.2	c.87C>A	p.Asn29Lys	missense_variant	1/13	ENST00000476941.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPC1	ENST00000476941.6	c.87C>A	p.Asn29Lys	missense_variant	1/13	1	NM_001251845.2	P1
TRPC1	ENST00000273482.10	c.87C>A	p.Asn29Lys	missense_variant	1/12	1
TRPC1	ENST00000698238.1	c.396C>A	p.Asn132Lys	missense_variant	1/13
TRPC1	ENST00000460401.1	c.84C>A	p.Asn28Lys	missense_variant, NMD_transcript_variant	1/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jul 11, 2023

The c.87C>A (p.N29K) alteration is located in exon 1 (coding exon 1) of the TRPC1 gene. This alteration results from a C to A substitution at nucleotide position 87, causing the asparagine (N) at amino acid position 29 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	Benign	0.14
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.16	T;.;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.74	T;.;T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.69	N;N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.070	N;N;.
REVEL	Benign	0.16
Sift	Uncertain	0.021	D;D;.
Sift4G	Benign	0.27	T;T;T
Polyphen		0.19	B;B;B
Vest4		0.44
MutPred		0.35		Gain of ubiquitination at N29 (P = 0.0054);Gain of ubiquitination at N29 (P = 0.0054);Gain of ubiquitination at N29 (P = 0.0054);
MVP		0.42
MPC		0.25
ClinPred		0.73	D
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.093
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: chr3-142443488;