12-2668602-A-G

Variant names:

• chr12-2668602-A-G
• rs6489375
• NM_000719.7:c.4624-331A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000719.7(CACNA1C):​c.4624-331A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.705 in 255,408 control chromosomes in the GnomAD database, including 69,555 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (37135 hom., cov: 31)
  • Exomes 𝑓: 0.78 (32420 hom.)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.14
• Publications: 3 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]

ITFG2-AS1 (HGNC:53128): (ITFG2 antisense RNA 1)

CACNA1C-AS2 (HGNC:40118): (CACNA1C antisense RNA 2)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 12-2668602-A-G is Benign according to our data. Variant chr12-2668602-A-G is described in ClinVar as Benign. ClinVar VariationId is 673266.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.824 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.4624-331A>G		intron	N/A	NP_000710.5
	CACNA1C	NM_001167623.2	MANE Plus Clinical	c.4624-331A>G		intron	N/A	NP_001161095.1	Q13936-37
	CACNA1C	NM_199460.4		c.4768-331A>G		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.4624-331A>G		intron	N/A	ENSP00000382512.1	Q13936-37
	CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.4624-331A>G		intron	N/A	ENSP00000382563.1	Q13936-12
	CACNA1C	ENST00000682544.1		c.4858-331A>G		intron	N/A	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes AF: 0.655 AC: 99518 AN: 151942 Hom.: 37137 Cov.: 31

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.632

Gnomad AMR AF: 0.715

Gnomad ASJ AF: 0.820

Gnomad EAS AF: 0.624

Gnomad SAS AF: 0.846

Gnomad FIN AF: 0.857

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.825

Gnomad OTH AF: 0.677

GnomAD4 exome AF: 0.779 AC: 80551 AN: 103348 Hom.: 32420 Cov.: 0 AF XY: 0.785 AC XY: 41441 AN XY: 52820

African (AFR) AF: 0.255 AC: 1030 AN: 4040

American (AMR) AF: 0.754 AC: 4028 AN: 5342

Ashkenazi Jewish (ASJ) AF: 0.814 AC: 2636 AN: 3238

East Asian (EAS) AF: 0.584 AC: 3794 AN: 6494

South Asian (SAS) AF: 0.846 AC: 7461 AN: 8824

European-Finnish (FIN) AF: 0.852 AC: 4441 AN: 5212

Middle Eastern (MID) AF: 0.783 AC: 368 AN: 470

European-Non Finnish (NFE) AF: 0.819 AC: 51961 AN: 63424

Other (OTH) AF: 0.766 AC: 4832 AN: 6304

GnomAD4 genome AF: 0.655 AC: 99527 AN: 152060 Hom.: 37135 Cov.: 31 AF XY: 0.659 AC XY: 49033 AN XY: 74354

African (AFR) AF: 0.268 AC: 11121 AN: 41454

American (AMR) AF: 0.715 AC: 10929 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.820 AC: 2847 AN: 3472

East Asian (EAS) AF: 0.623 AC: 3212 AN: 5154

South Asian (SAS) AF: 0.845 AC: 4071 AN: 4816

European-Finnish (FIN) AF: 0.857 AC: 9072 AN: 10586

Middle Eastern (MID) AF: 0.718 AC: 211 AN: 294

European-Non Finnish (NFE) AF: 0.825 AC: 56060 AN: 67984

Other (OTH) AF: 0.678 AC: 1430 AN: 2108

Alfa AF: 0.733 Hom.: 7386

Bravo AF: 0.624

Asia WGS AF: 0.707 AC: 2455 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.096
DANN	Benign	0.32
PhyloP100		-3.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6489375; hg19: chr12-2777768;