rs113239186

Positions:

• chr12-2682556-C-T

Variant summary

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

The NM_000719.7(CACNA1C):​c.5451C>T​(p.His1817His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00069 in 1,612,158 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (1 hom.)
• Consequence: CACNA1C NM_000719.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 2.21

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:):

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=-0.55).
• BP6: Variant 12-2682556-C-T is Benign according to our data. Variant chr12-2682556-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 93414.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2682556-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.21 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000644 (98/152256) while in subpopulation NFE AF= 0.00103 (70/68014). AF 95% confidence interval is 0.000835. There are 0 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 98 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5451C>T	p.His1817His	synonymous_variant	43/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5451C>T	p.His1817His	synonymous_variant	43/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5451C>T	p.His1817His	synonymous_variant	43/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5451C>T	p.His1817His	synonymous_variant	43/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5790C>T	p.His1930His	synonymous_variant	46/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5664C>T	p.His1888His	synonymous_variant	44/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5631C>T	p.His1877His	synonymous_variant	43/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5616C>T	p.His1872His	synonymous_variant	44/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5595C>T	p.His1865His	synonymous_variant	45/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5574C>T	p.His1858His	synonymous_variant	43/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5556C>T	p.His1852His	synonymous_variant	44/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5556C>T	p.His1852His	synonymous_variant	44/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5541C>T	p.His1847His	synonymous_variant	43/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5541C>T	p.His1847His	synonymous_variant	43/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5541C>T	p.His1847His	synonymous_variant	43/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5541C>T	p.His1847His	synonymous_variant	43/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5535C>T	p.His1845His	synonymous_variant	44/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5526C>T	p.His1842His	synonymous_variant	44/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5511C>T	p.His1837His	synonymous_variant	44/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5508C>T	p.His1836His	synonymous_variant	43/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5508C>T	p.His1836His	synonymous_variant	43/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5508C>T	p.His1836His	synonymous_variant	43/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5502C>T	p.His1834His	synonymous_variant	43/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5493C>T	p.His1831His	synonymous_variant	43/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5475C>T	p.His1825His	synonymous_variant	42/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5475C>T	p.His1825His	synonymous_variant	42/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5469C>T	p.His1823His	synonymous_variant	42/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5451C>T	p.His1817His	synonymous_variant	43/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5451C>T	p.His1817His	synonymous_variant	43/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5451C>T	p.His1817His	synonymous_variant	43/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5451C>T	p.His1817His	synonymous_variant	43/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5451C>T	p.His1817His	synonymous_variant	43/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5442C>T	p.His1814His	synonymous_variant	43/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5418C>T	p.His1806His	synonymous_variant	42/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.000507 AC: 125 AN: 246362 Hom.: 0 AF XY: 0.000472 AC XY: 63 AN XY: 133578

Gnomad AFR exome AF: 0.000196

Gnomad AMR exome AF: 0.000322

Gnomad ASJ exome AF: 0.0000999

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000165

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000902

Gnomad OTH exome AF: 0.000665

GnomAD4 exome AF: 0.000695 AC: 1015 AN: 1459902 Hom.: 1 Cov.: 31 AF XY: 0.000691 AC XY: 502 AN XY: 726092

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000539

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000163

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000796

Gnomad4 OTH exome AF: 0.00104

GnomAD4 genome AF: 0.000644 AC: 98 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.000511 AC XY: 38 AN XY: 74416

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00103

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000851 Hom.: 0

Bravo AF: 0.000620

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	CACNA1C: BP4, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 12, 2019	- -

CACNA1C-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 20, 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). -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2016

This alteration is classified as likely 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	-0.55
CADD	Benign	6.3
DANN	Benign	0.70

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: rs113239186; hg19: chr12-2791722;