12-2293080-A-G

Variant names:

• chr12-2293080-A-G
• rs1024582
• NM_000719.7:c.478-155896A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000719.7(CACNA1C):​c.478-155896A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.748 in 152,060 control chromosomes in the GnomAD database, including 43,595 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.75 (43595 hom., cov: 31)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.743
• Publications: 35 publications found

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-IT3 (HGNC:41314): (CACNA1C intronic transcript 3)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.935 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000719.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	NM_000719.7	MANE Select	c.478-155896A>G		intron	N/A	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.478-155896A>G		intron	N/A	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.478-155896A>G		intron	N/A	NP_955630.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	ENST00000399603.6	TSL:5 MANE Plus Clinical	c.478-155896A>G		intron	N/A	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.478-155896A>G		intron	N/A	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.568-155896A>G		intron	N/A	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes AF: 0.748 AC: 113654 AN: 151942 Hom.: 43539 Cov.: 31

Gnomad AFR AF: 0.893

Gnomad AMI AF: 0.654

Gnomad AMR AF: 0.756

Gnomad ASJ AF: 0.713

Gnomad EAS AF: 0.956

Gnomad SAS AF: 0.764

Gnomad FIN AF: 0.672

Gnomad MID AF: 0.801

Gnomad NFE AF: 0.656

Gnomad OTH AF: 0.761

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.748 AC: 113772 AN: 152060 Hom.: 43595 Cov.: 31 AF XY: 0.752 AC XY: 55843 AN XY: 74296

African (AFR) AF: 0.893 AC: 37045 AN: 41500

American (AMR) AF: 0.756 AC: 11554 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.713 AC: 2474 AN: 3472

East Asian (EAS) AF: 0.957 AC: 4945 AN: 5168

South Asian (SAS) AF: 0.764 AC: 3677 AN: 4814

European-Finnish (FIN) AF: 0.672 AC: 7083 AN: 10542

Middle Eastern (MID) AF: 0.793 AC: 233 AN: 294

European-Non Finnish (NFE) AF: 0.656 AC: 44556 AN: 67966

Other (OTH) AF: 0.764 AC: 1610 AN: 2106

Alfa AF: 0.704 Hom.: 95295

Bravo AF: 0.765

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.0
DANN	Benign	0.67
PhyloP100		-0.74
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1024582; hg19: chr12-2402246;