rs2238092

chr12-2614100-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000719.7(CACNA1C):c.3828+2087G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.641 in 152,054 control chromosomes in the GnomAD database, including 33,668 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 0.64 (33662 hom., cov: 31)
  • Exomes 𝑓: 0.80 (6 hom.)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.54

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.766 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7	c.3828+2087G>A		intron_variant		ENST00000399655.6
CACNA1C	NM_001167623.2	c.3828+2087G>A		intron_variant		ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3828+2087G>A		intron_variant		5	NM_001167623.2
CACNA1C	ENST00000399655.6	c.3828+2087G>A		intron_variant		1	NM_000719.7

Frequencies

GnomAD3 genomes AF: 0.641 AC: 97396 AN: 151914 Hom.: 33654 Cov.: 31

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.711

Gnomad AMR AF: 0.679

Gnomad ASJ AF: 0.706

Gnomad EAS AF: 0.654

Gnomad SAS AF: 0.690

Gnomad FIN AF: 0.769

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.772

Gnomad OTH AF: 0.644

GnomAD4 exome AF: 0.800 AC: 16 AN: 20 Hom.: 6 Cov.: 0 AF XY: 0.800 AC XY: 8 AN XY: 10

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.778

GnomAD4 genome AF: 0.641 AC: 97435 AN: 152034 Hom.: 33662 Cov.: 31 AF XY: 0.642 AC XY: 47679 AN XY: 74320

Gnomad4 AFR AF: 0.365

Gnomad4 AMR AF: 0.679

Gnomad4 ASJ AF: 0.706

Gnomad4 EAS AF: 0.654

Gnomad4 SAS AF: 0.689

Gnomad4 FIN AF: 0.769

Gnomad4 NFE AF: 0.772

Gnomad4 OTH AF: 0.645

Alfa AF: 0.736 Hom.: 58877

Bravo AF: 0.624

Asia WGS AF: 0.694 AC: 2411 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.049
Dann	Benign	0.63

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: rs2238092; hg19: chr12-2723266;