rs34621387

Positions:

• chr12-2419238-A-G

Variant summary

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

The NM_000719.7(CACNA1C):​c.478-29738A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.423 in 151,998 control chromosomes in the GnomAD database, including 13,818 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 0.42 (13818 hom., cov: 32)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.79

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=-1.07).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.478-29738A>G		intron_variant		ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.478-29738A>G		intron_variant		ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.478-29738A>G		intron_variant		5	NM_001167623.2	ENSP00000382512
CACNA1C	ENST00000399655.6	c.478-29738A>G		intron_variant		1	NM_000719.7	ENSP00000382563

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64301 AN: 151880 Hom.: 13802 Cov.: 32

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.482

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.512

Gnomad EAS AF: 0.243

Gnomad SAS AF: 0.332

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.443

Gnomad OTH AF: 0.420

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

GnomAD4 genome AF: 0.423 AC: 64351 AN: 151998 Hom.: 13818 Cov.: 32 AF XY: 0.421 AC XY: 31249 AN XY: 74308

Gnomad4 AFR AF: 0.420

Gnomad4 AMR AF: 0.394

Gnomad4 ASJ AF: 0.512

Gnomad4 EAS AF: 0.243

Gnomad4 SAS AF: 0.333

Gnomad4 FIN AF: 0.446

Gnomad4 NFE AF: 0.443

Gnomad4 OTH AF: 0.425

Alfa AF: 0.429 Hom.: 1750

Bravo AF: 0.420

Asia WGS AF: 0.351 AC: 1220 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.33
DANN	Benign	0.13

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: rs34621387; hg19: chr12-2528404;