rs576194052

chr12-2566592-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.1669+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000849 in 1,588,314 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (9 hom.)
• Consequence: CACNA1C NM_000719.7 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.289

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 12-2566592-G-A is Benign according to our data. Variant chr12-2566592-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 527033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00169 (257/152250) while in subpopulation EAS AF= 0.000965 (5/5182). AF 95% confidence interval is 0.00038. There are 6 homozygotes in gnomad4. There are 195 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 257 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7	c.1669+10G>A		intron_variant		ENST00000399655.6
CACNA1C	NM_001167623.2	c.1669+10G>A		intron_variant		ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1669+10G>A		intron_variant		5	NM_001167623.2
CACNA1C	ENST00000399655.6	c.1669+10G>A		intron_variant		1	NM_000719.7

Frequencies

GnomAD3 genomes AF: 0.00169 AC: 257 AN: 152132 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0212

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00180 AC: 377 AN: 209888 Hom.: 3 AF XY: 0.00181 AC XY: 205 AN XY: 113136

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000395

Gnomad SAS exome AF: 0.0000394

Gnomad FIN exome AF: 0.0170

Gnomad NFE exome AF: 0.000464

Gnomad OTH exome AF: 0.000752

GnomAD4 exome AF: 0.000760 AC: 1092 AN: 1436064 Hom.: 9 Cov.: 30 AF XY: 0.000770 AC XY: 548 AN XY: 711758

Gnomad4 AFR exome AF: 0.000122

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000550

Gnomad4 SAS exome AF: 0.0000979

Gnomad4 FIN exome AF: 0.0166

Gnomad4 NFE exome AF: 0.000145

Gnomad4 OTH exome AF: 0.000759

GnomAD4 genome AF: 0.00169 AC: 257 AN: 152250 Hom.: 6 Cov.: 33 AF XY: 0.00262 AC XY: 195 AN XY: 74442

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0212

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000475 Hom.: 0

Bravo AF: 0.0000982

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 11, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 23, 2023	- -

CACNA1C-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 26, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	0.18
Dann	Benign	0.73

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: rs576194052; hg19: chr12-2675758;