rs16929277

chr12-2331006-C-G

Variant summary

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

The NM_000719.7(CACNA1C):c.478-117970C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 152,010 control chromosomes in the GnomAD database, including 2,855 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 0.12 (2855 hom., cov: 33)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.280

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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7	c.478-117970C>G		intron_variant		ENST00000399655.6
CACNA1C	NM_001167623.2	c.478-117970C>G		intron_variant		ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6	c.478-117970C>G		intron_variant		5	NM_001167623.2
CACNA1C	ENST00000399655.6	c.478-117970C>G		intron_variant		1	NM_000719.7

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17950 AN: 151892 Hom.: 2837 Cov.: 33

Gnomad AFR AF: 0.364

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0786

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.0245

Gnomad SAS AF: 0.0166

Gnomad FIN AF: 0.0146

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0164

Gnomad OTH AF: 0.0962

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

GnomAD4 genome AF: 0.119 AC: 18018 AN: 152010 Hom.: 2855 Cov.: 33 AF XY: 0.115 AC XY: 8569 AN XY: 74320

Gnomad4 AFR AF: 0.364

Gnomad4 AMR AF: 0.0783

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.0245

Gnomad4 SAS AF: 0.0164

Gnomad4 FIN AF: 0.0146

Gnomad4 NFE AF: 0.0164

Gnomad4 OTH AF: 0.102

Alfa AF: 0.0773 Hom.: 218

Bravo AF: 0.136

Asia WGS AF: 0.0860 AC: 301 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	4.9
Dann	Benign	0.73

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: rs16929277; hg19: chr12-2440172;