3-142724623-T-C

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.64T>C(p.Ser22Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,459,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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: 0.000045 (0 hom.)
• Consequence: TRPC1 NM_001251845.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.79

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=0.116077095).
• BS2: High AC in GnomAdExome at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPC1	NM_001251845.2	c.64T>C	p.Ser22Pro	missense_variant	1/13	ENST00000476941.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPC1	ENST00000476941.6	c.64T>C	p.Ser22Pro	missense_variant	1/13	1	NM_001251845.2	P1
TRPC1	ENST00000273482.10	c.64T>C	p.Ser22Pro	missense_variant	1/12	1
TRPC1	ENST00000698238.1	c.373T>C	p.Ser125Pro	missense_variant	1/13
TRPC1	ENST00000460401.1	c.61T>C	p.Ser21Pro	missense_variant, NMD_transcript_variant	1/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000683 AC: 17 AN: 248858 Hom.: 0 AF XY: 0.000126 AC XY: 17 AN XY: 134770

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: 0.000558

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000452 AC: 66 AN: 1459764 Hom.: 0 Cov.: 31 AF XY: 0.0000661 AC XY: 48 AN XY: 726168

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: 0.000709

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000830

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.0000659 AC: 8

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

Oct 12, 2021

The c.64T>C (p.S22P) alteration is located in exon 1 (coding exon 1) of the TRPC1 gene. This alteration results from a T to C substitution at nucleotide position 64, causing the serine (S) at amino acid position 22 to be replaced by a proline (P). 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	0.078
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.73	T;.;T
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.55	N;N;N
MutationTaster	Benign	0.97	N;N
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.69	N;N;.
REVEL	Uncertain	0.32
Sift	Benign	0.073	T;T;.
Sift4G	Benign	0.13	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.42
MutPred		0.26		Loss of phosphorylation at S22 (P = 0.0011);Loss of phosphorylation at S22 (P = 0.0011);Loss of phosphorylation at S22 (P = 0.0011);
MVP		0.58
MPC		0.29
ClinPred		0.050	T
GERP RS		2.3
Varity_R		0.12
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs760081567; hg19: chr3-142443465;