rs2283274

Positions:

• chr12-2075300-G-C
• chr12-2075300-G-T

Variant summary

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

The NM_000719.7(CACNA1C):​c.49+21689G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.216 in 152,098 control chromosomes in the GnomAD database, including 3,929 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 0.22 (3929 hom., cov: 32)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.311

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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7	c.49+21689G>C		intron_variant		ENST00000399655.6
CACNA1C	NM_001167623.2	c.49+21689G>C		intron_variant		ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6	c.49+21689G>C		intron_variant		5	NM_001167623.2
CACNA1C	ENST00000399655.6	c.49+21689G>C		intron_variant		1	NM_000719.7

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32741 AN: 151980 Hom.: 3925 Cov.: 32

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.162

Gnomad EAS AF: 0.441

Gnomad SAS AF: 0.230

Gnomad FIN AF: 0.255

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.197

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

GnomAD4 genome AF: 0.216 AC: 32786 AN: 152098 Hom.: 3929 Cov.: 32 AF XY: 0.221 AC XY: 16412 AN XY: 74354

Gnomad4 AFR AF: 0.287

Gnomad4 AMR AF: 0.152

Gnomad4 ASJ AF: 0.162

Gnomad4 EAS AF: 0.442

Gnomad4 SAS AF: 0.229

Gnomad4 FIN AF: 0.255

Gnomad4 NFE AF: 0.166

Gnomad4 OTH AF: 0.200

Alfa AF: 0.189 Hom.: 358

Bravo AF: 0.212

Asia WGS AF: 0.339 AC: 1179 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.8
DANN	Benign	0.44

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: rs2283274; hg19: chr12-2184466;