12-2223044-C-T

Variant names:

• chr12-2223044-C-T
• rs2239028
• NM_000719.7:c.477+102614C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000719.7(CACNA1C):​c.477+102614C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 152,122 control chromosomes in the GnomAD database, including 1,991 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 0.14 (1991 hom., cov: 33)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.308
• Publications: 5 publications found

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]

CACNA1C-AS4 (HGNC:40116): (CACNA1C antisense RNA 4)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000719.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	NM_000719.7	MANE Select	c.477+102614C>T		intron	N/A	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.477+102614C>T		intron	N/A	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.477+102614C>T		intron	N/A	NP_955630.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1C	ENST00000399603.6	TSL:5 MANE Plus Clinical	c.477+102614C>T		intron	N/A	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.477+102614C>T		intron	N/A	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.567+102614C>T		intron	N/A	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes AF: 0.139 AC: 21155 AN: 152004 Hom.: 1972 Cov.: 33

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.220

Gnomad FIN AF: 0.0443

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.0755

Gnomad OTH AF: 0.150

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

GnomAD4 genome AF: 0.140 AC: 21229 AN: 152122 Hom.: 1991 Cov.: 33 AF XY: 0.140 AC XY: 10429 AN XY: 74374

African (AFR) AF: 0.232 AC: 9625 AN: 41416

American (AMR) AF: 0.165 AC: 2522 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 383 AN: 3472

East Asian (EAS) AF: 0.298 AC: 1543 AN: 5180

South Asian (SAS) AF: 0.220 AC: 1062 AN: 4820

European-Finnish (FIN) AF: 0.0443 AC: 470 AN: 10612

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.0755 AC: 5133 AN: 68010

Other (OTH) AF: 0.161 AC: 339 AN: 2110

Alfa AF: 0.0960 Hom.: 1569

Bravo AF: 0.152

Asia WGS AF: 0.286 AC: 995 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	2.1
DANN	Benign	0.49
PhyloP100		-0.31
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2239028; hg19: chr12-2332210;