12-2053575-AAT-A

Variant names:

• chr12-2053575-AAT-A
• rs786205782
• NM_000719.7:c.15_16delTA

Variant summary

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

The NM_000719.7(CACNA1C):​c.15_16delTA​(p.Thr6GlufsTer35) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000181 in 1,600,686 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: CACNA1C NM_000719.7 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3
• Conservation: PhyloP100: 2.18

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 41 pathogenic variants in the truncated region.
• BS2: High AC in GnomAdExome4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000406454.8	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000347598.9	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000399638.5	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.15_16delTA	p.Thr6GlufsTer35	frameshift_variant	Exon 1 of 46			ENSP00000507309.1
CACNA1C	ENST00000682544.1	c.140-61647_140-61646delTA		intron_variant	Intron 1 of 49			ENSP00000507184.1
CACNA1C	ENST00000683824.1	c.140-61647_140-61646delTA		intron_variant	Intron 1 of 47			ENSP00000507867.1
CACNA1C	ENST00000682462.1	c.140-61647_140-61646delTA		intron_variant	Intron 1 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.140-61647_140-61646delTA		intron_variant	Intron 1 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.140-61647_140-61646delTA		intron_variant	Intron 1 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.140-61647_140-61646delTA		intron_variant	Intron 1 of 46			ENSP00000506882.1
CACNA1C	ENST00000480911.6	n.15_16delTA		non_coding_transcript_exon_variant	Exon 1 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152036 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: 0.00000883 AC: 2 AN: 226604 Hom.: 0 AF XY: 0.00000815 AC XY: 1 AN XY: 122720

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000198

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000186 AC: 27 AN: 1448650 Hom.: 0 AF XY: 0.0000139 AC XY: 10 AN XY: 719244

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000244

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152036 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74274

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: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

CACNA1C-related disorder Pathogenic:1

Aug 27, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CACNA1C c.15_16delTA variant is predicted to result in a frameshift and premature protein termination (p.Thr6Glufs*35). This variant was reported in an individual with atrial fibrillation (Yoneda et al 2021. PubMed ID: 34495297). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in CACNA1C are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

not provided Pathogenic:1

Feb 26, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in an individual from a cohort with early onset atrial fibrillation in published literature (PMID: 34495297); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34495297) -

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

Oct 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Uncertain:1

Sep 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Thr6Glufs*35) in the CACNA1C gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in CACNA1C cause disease. This variant is present in population databases (rs786205782, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with atrial fibrillation (PMID: 34495297). ClinVar contains an entry for this variant (Variation ID: 190711). 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. -

Cardiovascular phenotype Uncertain:1

Dec 08, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.15_16delTA variant, located in coding exon 1 of the CACNA1C gene, results from a deletion of two nucleotides at nucleotide positions 15 to 16, causing a translational frameshift with a predicted alternate stop codon (p.T6Efs*35). The predicted stop codon occurs in the 5&rsquo; end of theCACNA1C gene. Premature termination codons in the 5&rsquo; end of a gene have been reported to escape nonsense-mediated mRNAdecay and/or lead to re-initiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). The exact functional effect of this alteration is unknown. According to data from gnomAD, the frequency for this variant is above the maximum credible frequency for a cardiac disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Based on the supporting evidence, the association of this alteration with CACNA1C-related neurodevelopmental disorder is unknown; however, the association with CACNA1C-related long QT syndrome or Timothy syndrome is unlikely. -

Computational scores

Source: dbNSFP v4.3

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: rs786205782; hg19: chr12-2162741;