12-2053564-T-C

Position:

• chr12-2053564-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 8P and 4B. PVS1 BS2

The NM_000719.7(CACNA1C):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000545 in 1,596,754 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000059 (0 hom.)
• Consequence: CACNA1C NM_000719.7 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 2.31

Genes affected

CACNA1C (HGNC:1390): (calcium voltage-gated channel subunit alpha1 C) This gene encodes an alpha-1 subunit of a voltage-dependent calcium channel. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. The alpha-1 subunit consists of 24 transmembrane segments and forms the pore through which ions pass into the cell. The calcium channel consists of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. There are multiple isoforms of each of these proteins, either encoded by different genes or the result of alternative splicing of transcripts. The protein encoded by this gene binds to and is inhibited by dihydropyridine. Alternative splicing results in many transcript variants encoding different proteins. Some of the predicted proteins may not produce functional ion channel subunits. [provided by RefSeq, Oct 2012]

CACNA1C (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• BS2: High AC in GnomAdExome4 at 85 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2T>C	p.Met1?	start_lost	1/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2T>C	p.Met1?	start_lost	1/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2T>C	p.Met1?	start_lost	1/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2T>C	p.Met1?	start_lost	1/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000406454.8	c.2T>C	p.Met1?	start_lost	1/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2T>C	p.Met1?	start_lost	1/47	5		ENSP00000382542.2
CACNA1C	ENST00000347598.9	c.2T>C	p.Met1?	start_lost	1/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2T>C	p.Met1?	start_lost	1/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2T>C	p.Met1?	start_lost	1/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2T>C	p.Met1?	start_lost	1/48	5		ENSP00000382526.1
CACNA1C	ENST00000399638.5	c.2T>C	p.Met1?	start_lost	1/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.2T>C	p.Met1?	start_lost	1/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.2T>C	p.Met1?	start_lost	1/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2T>C	p.Met1?	start_lost	1/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2T>C	p.Met1?	start_lost	1/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2T>C	p.Met1?	start_lost	1/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2T>C	p.Met1?	start_lost	1/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.2T>C	p.Met1?	start_lost	1/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2T>C	p.Met1?	start_lost	1/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2T>C	p.Met1?	start_lost	1/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2T>C	p.Met1?	start_lost	1/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2T>C	p.Met1?	start_lost	1/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2T>C	p.Met1?	start_lost	1/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2T>C	p.Met1?	start_lost	1/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2T>C	p.Met1?	start_lost	1/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2T>C	p.Met1?	start_lost	1/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2T>C	p.Met1?	start_lost	1/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2T>C	p.Met1?	start_lost	1/46			ENSP00000507309.1
CACNA1C	ENST00000682544.1	c.140-61660T>C		intron_variant				ENSP00000507184.1
CACNA1C	ENST00000683824.1	c.140-61660T>C		intron_variant				ENSP00000507867.1
CACNA1C	ENST00000682462.1	c.140-61660T>C		intron_variant				ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.140-61660T>C		intron_variant				ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.140-61660T>C		intron_variant				ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.140-61660T>C		intron_variant				ENSP00000506882.1
CACNA1C	ENST00000480911.6	n.2T>C		non_coding_transcript_exon_variant	1/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152104 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000225 AC: 5 AN: 222384 Hom.: 0 AF XY: 0.0000250 AC XY: 3 AN XY: 120202

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: 0.0000371

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000302

Gnomad OTH exome AF: 0.000181

GnomAD4 exome AF: 0.0000588 AC: 85 AN: 1444650 Hom.: 0 Cov.: 32 AF XY: 0.0000474 AC XY: 34 AN XY: 716894

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000725

Gnomad4 OTH exome AF: 0.0000502

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152104 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74314

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000189

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 27, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2024	Not observed at significant frequency in large population cohorts (gnomAD); Initiation codon variant in a gene for which loss of function is not a known mechanism of disease; Has not been previously published in association with Timothy syndrome or LQTS to our knowledge; This variant is associated with the following publications: (PMID: 26637798) -

Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 16, 2021

- -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 03, 2023

This variant is present in population databases (rs761378545, gnomAD 0.004%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 190710). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. This sequence change affects the initiator methionine of the CACNA1C mRNA. The next in-frame methionine is located at codon 8. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.021	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Benign	0.098
Eigen_PC	Benign	0.082
FATHMM_MKL	Benign	0.57	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.89	D
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.60, 0.025, 0.056, 0.81	.;P;.;B;P;B;P;P;P;P;P;P;P;P;P;P;.;P;P;.;.;.;.
Vest4		0.67
MutPred		0.98		Gain of catalytic residue at M1 (P = 0.0137);Gain of catalytic residue at M1 (P = 0.0137);Gain of catalytic residue at M1 (P = 0.0137);Gain of catalytic residue at M1 (P = 0.0137);Gain of catalytic residue at M1 (P = 0.0137);Gain of catalytic residue at M1 (P = 0.0137);Gain of catalytic residue at M1 (P = 0.0137);Gain of catalytic residue at M1 (P = 0.0137);Gain of catalytic residue at M1 (P = 0.0137);Gain of catalytic residue at M1 (P = 0.0137);Gain of catalytic residue at M1 (P = 0.0137);Gain of catalytic residue at M1 (P = 0.0137);Gain of catalytic residue at M1 (P = 0.0137);Gain of catalytic residue at M1 (P = 0.0137);Gain of catalytic residue at M1 (P = 0.0137);Gain of catalytic residue at M1 (P = 0.0137);Gain of catalytic residue at M1 (P = 0.0137);Gain of catalytic residue at M1 (P = 0.0137);Gain of catalytic residue at M1 (P = 0.0137);Gain of catalytic residue at M1 (P = 0.0137);Gain of catalytic residue at M1 (P = 0.0137);Gain of catalytic residue at M1 (P = 0.0137);Gain of catalytic residue at M1 (P = 0.0137);
MVP		0.94
ClinPred		0.95	D
GERP RS		3.0
gMVP		0.69

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: rs761378545; hg19: chr12-2162730; COSMIC: COSV59737906; COSMIC: COSV59737906;