rs11062316

Positions:

• chr12-2685766-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000399655.6(CACNA1C):​c.5604A>G​(p.Gln1868=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,613,738 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (19 hom.)
• Consequence: CACNA1C ENST00000399655.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.284

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-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 12-2685766-A-G is Benign according to our data. Variant chr12-2685766-A-G is described in ClinVar as [Benign]. Clinvar id is 93415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2685766-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.284 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00882 (1343/152322) while in subpopulation AFR AF= 0.0304 (1262/41578). AF 95% confidence interval is 0.029. There are 21 homozygotes in gnomad4. There are 651 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1343 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5604A>G	p.Gln1868=	synonymous_variant	44/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5604A>G	p.Gln1868=	synonymous_variant	44/47	ENST00000399603.6	NP_001161095.1
CACNA1C-AS1	NR_045725.1	n.333+4374T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5604A>G	p.Gln1868=	synonymous_variant	44/47	5	NM_001167623.2	ENSP00000382512
CACNA1C	ENST00000399655.6	c.5604A>G	p.Gln1868=	synonymous_variant	44/47	1	NM_000719.7	ENSP00000382563
CACNA1C-AS1	ENST00000501371.5	n.294+4374T>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.00881 AC: 1341 AN: 152204 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0304

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00216 AC: 537 AN: 248892 Hom.: 7 AF XY: 0.00164 AC XY: 221 AN XY: 135040

Gnomad AFR exome AF: 0.0292

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000976

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00107 AC: 1558 AN: 1461416 Hom.: 19 Cov.: 31 AF XY: 0.000920 AC XY: 669 AN XY: 727012

Gnomad4 AFR exome AF: 0.0344

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000111

Gnomad4 OTH exome AF: 0.00255

GnomAD4 genome AF: 0.00882 AC: 1343 AN: 152322 Hom.: 21 Cov.: 32 AF XY: 0.00874 AC XY: 651 AN XY: 74474

Gnomad4 AFR AF: 0.0304

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00433 Hom.: 4

Bravo AF: 0.0100

EpiCase AF: 0.000382

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 21, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 27, 2017	Variant summary: The CACNA1C c.5604A>G (p.Gln1868Gln) variant causes a synonymous change involving a non-conserved nucleotide, which 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may alter ESE binding. However, the variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 335/120470 (7 homozygotes, 1/359), which significantly exceeds the estimated maximal expected allele frequency of a pathogenic CACNA1C variant of 1/100000. Therefore, suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories classified this variant as "likely benign/benign." Therefore, the variant of interest has been classified as Benign. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 11, 2013

- -

Long QT syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.90
DANN	Benign	0.58

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: rs11062316; hg19: chr12-2794932;