12-2685819-G-C

Variant names:

• chr12-2685819-G-C
• rs748198629
• NM_000719.7:c.5657G>C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_000719.7(CACNA1C):​c.5657G>C​(p.Gly1886Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000316 in 1,613,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.50

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-AS1 (HGNC:):

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant in the CACNA1C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. Gene score misZ: 6.4654 (above the threshold of 3.09). Trascript score misZ: 7.2674 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, Brugada syndrome, long QT syndrome, short QT syndrome, long qt syndrome 8, Timothy syndrome, Brugada syndrome 3.
• BP4: Computational evidence support a benign effect (MetaRNN=0.10530129).
• BS2: High AC in GnomAdExome4 at 49 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5657G>C	p.Gly1886Ala	missense_variant	Exon 44 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5657G>C	p.Gly1886Ala	missense_variant	Exon 44 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5657G>C	p.Gly1886Ala	missense_variant	Exon 44 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5657G>C	p.Gly1886Ala	missense_variant	Exon 44 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5996G>C	p.Gly1999Ala	missense_variant	Exon 47 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5870G>C	p.Gly1957Ala	missense_variant	Exon 45 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5837G>C	p.Gly1946Ala	missense_variant	Exon 44 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5822G>C	p.Gly1941Ala	missense_variant	Exon 45 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5801G>C	p.Gly1934Ala	missense_variant	Exon 46 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5780G>C	p.Gly1927Ala	missense_variant	Exon 44 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5762G>C	p.Gly1921Ala	missense_variant	Exon 45 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5762G>C	p.Gly1921Ala	missense_variant	Exon 45 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5747G>C	p.Gly1916Ala	missense_variant	Exon 44 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5747G>C	p.Gly1916Ala	missense_variant	Exon 44 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5747G>C	p.Gly1916Ala	missense_variant	Exon 44 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5747G>C	p.Gly1916Ala	missense_variant	Exon 44 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5741G>C	p.Gly1914Ala	missense_variant	Exon 45 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5732G>C	p.Gly1911Ala	missense_variant	Exon 45 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5717G>C	p.Gly1906Ala	missense_variant	Exon 45 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5714G>C	p.Gly1905Ala	missense_variant	Exon 44 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5714G>C	p.Gly1905Ala	missense_variant	Exon 44 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5714G>C	p.Gly1905Ala	missense_variant	Exon 44 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5708G>C	p.Gly1903Ala	missense_variant	Exon 44 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5699G>C	p.Gly1900Ala	missense_variant	Exon 44 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5681G>C	p.Gly1894Ala	missense_variant	Exon 43 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5681G>C	p.Gly1894Ala	missense_variant	Exon 43 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5675G>C	p.Gly1892Ala	missense_variant	Exon 43 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5657G>C	p.Gly1886Ala	missense_variant	Exon 44 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5657G>C	p.Gly1886Ala	missense_variant	Exon 44 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5657G>C	p.Gly1886Ala	missense_variant	Exon 44 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5657G>C	p.Gly1886Ala	missense_variant	Exon 44 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5657G>C	p.Gly1886Ala	missense_variant	Exon 44 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5648G>C	p.Gly1883Ala	missense_variant	Exon 44 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5624G>C	p.Gly1875Ala	missense_variant	Exon 43 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152216 Hom.: 0 Cov.: 32

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: 0.00000402 AC: 1 AN: 248882 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 135030

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: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000335 AC: 49 AN: 1460970 Hom.: 0 Cov.: 31 AF XY: 0.0000316 AC XY: 23 AN XY: 726818

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: 0.0000441

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74364

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

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Uncertain:1

Nov 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1886 of the CACNA1C protein (p.Gly1886Ala). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 566792). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CACNA1C protein function with a negative predictive value of 95%. 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

Oct 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G1886A variant (also known as c.5657G>C), located in coding exon 44 of the CACNA1C gene, results from a G to C substitution at nucleotide position 5657. The glycine at codon 1886 is replaced by alanine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Benign	0.68
DEOGEN2	Benign	0.0026	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.080	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.14
Sift	Benign	0.98	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.60	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0, 0.12	.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;B;.
Vest4		0.20
MVP		0.66
MPC		0.21
ClinPred		0.11	T
GERP RS		4.3
gMVP		0.38

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: rs748198629; hg19: chr12-2794985;