rs2283275

Positions:

• chr12-2075394-C-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+21783C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.768 in 152,060 control chromosomes in the GnomAD database, including 45,368 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 0.77 (45368 hom., cov: 31)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.389

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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.839 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7	c.49+21783C>T		intron_variant		ENST00000399655.6
CACNA1C	NM_001167623.2	c.49+21783C>T		intron_variant		ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6	c.49+21783C>T		intron_variant		5	NM_001167623.2
CACNA1C	ENST00000399655.6	c.49+21783C>T		intron_variant		1	NM_000719.7

Frequencies

GnomAD3 genomes AF: 0.768 AC: 116722 AN: 151942 Hom.: 45321 Cov.: 31

Gnomad AFR AF: 0.846

Gnomad AMI AF: 0.602

Gnomad AMR AF: 0.679

Gnomad ASJ AF: 0.820

Gnomad EAS AF: 0.515

Gnomad SAS AF: 0.674

Gnomad FIN AF: 0.700

Gnomad MID AF: 0.829

Gnomad NFE AF: 0.777

Gnomad OTH AF: 0.772

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

GnomAD4 genome AF: 0.768 AC: 116825 AN: 152060 Hom.: 45368 Cov.: 31 AF XY: 0.760 AC XY: 56465 AN XY: 74330

Gnomad4 AFR AF: 0.846

Gnomad4 AMR AF: 0.678

Gnomad4 ASJ AF: 0.820

Gnomad4 EAS AF: 0.516

Gnomad4 SAS AF: 0.673

Gnomad4 FIN AF: 0.700

Gnomad4 NFE AF: 0.777

Gnomad4 OTH AF: 0.774

Alfa AF: 0.766 Hom.: 22573

Bravo AF: 0.772

Asia WGS AF: 0.625 AC: 2177 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.1
DANN	Benign	0.65

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: rs2283275; hg19: chr12-2184560;