12-2605587-G-A

Position:

• chr12-2605587-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000719.7(CACNA1C):​c.3049-92G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 888,450 control chromosomes in the GnomAD database, including 371 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (56 hom., cov: 32)
  • Exomes 𝑓: 0.018 (315 hom.)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.805

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-AS3 (HGNC:40117): (CACNA1C antisense RNA 3)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-2605587-G-A is Benign according to our data. Variant chr12-2605587-G-A is described in ClinVar as [Benign]. Clinvar id is 1227836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0165 (2504/152158) while in subpopulation NFE AF= 0.016 (1088/67996). AF 95% confidence interval is 0.0152. There are 56 homozygotes in gnomad4. There are 1479 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2504 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7	c.3049-92G>A		intron_variant		ENST00000399655.6
CACNA1C	NM_001167623.2	c.3049-92G>A		intron_variant		ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3049-92G>A		intron_variant		5	NM_001167623.2
CACNA1C	ENST00000399655.6	c.3049-92G>A		intron_variant		1	NM_000719.7
CACNA1C-AS3	ENST00000543559.1	n.21-1814C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2505 AN: 152040 Hom.: 56 Cov.: 32

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.00929

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0985

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.0120

GnomAD4 exome AF: 0.0182 AC: 13415 AN: 736292 Hom.: 315 AF XY: 0.0171 AC XY: 6681 AN XY: 390444

Gnomad4 AFR exome AF: 0.00232

Gnomad4 AMR exome AF: 0.00487

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00188

Gnomad4 FIN exome AF: 0.0958

Gnomad4 NFE exome AF: 0.0163

Gnomad4 OTH exome AF: 0.0170

GnomAD4 genome AF: 0.0165 AC: 2504 AN: 152158 Hom.: 56 Cov.: 32 AF XY: 0.0199 AC XY: 1479 AN XY: 74372

Gnomad4 AFR AF: 0.00275

Gnomad4 AMR AF: 0.00928

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0985

Gnomad4 NFE AF: 0.0160

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0170 Hom.: 4

Bravo AF: 0.0101

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.58
DANN	Benign	0.51

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: rs41276704; hg19: chr12-2714753;