12-2681966-A-G

Variant names:

• chr12-2681966-A-G
• rs10774053
• ENST00000682544.1:c.5695A>G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_199460.4(CACNA1C):​c.5605A>G​(p.Met1869Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.82 in 1,598,268 control chromosomes in the GnomAD database, including 539,546 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.80 (48930 hom., cov: 31)
  • Exomes 𝑓: 0.82 (490616 hom.)
• Consequence: CACNA1C NM_199460.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.521

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 -19 ACMG points.

• PP2: Missense variant in the CACNA1C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. Gene score misZ: 6.4654 (above the threshold of 3.09). Trascript score misZ: 7.225 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, Brugada syndrome, long QT syndrome, short QT syndrome, long qt syndrome 8, Timothy syndrome, Brugada syndrome 3.
• BP4: Computational evidence support a benign effect (MetaRNN=2.4774297E-6).
• BP6: Variant 12-2681966-A-G is Benign according to our data. Variant chr12-2681966-A-G is described in ClinVar as [Benign]. Clinvar id is 136639.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2681966-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.836 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5445-584A>G		intron_variant	Intron 42 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5445-584A>G		intron_variant	Intron 42 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000682544.1	c.5695A>G	p.Met1899Val	missense_variant	Exon 45 of 50			ENSP00000507184.1
CACNA1C	ENST00000327702.12	c.5461A>G	p.Met1821Val	missense_variant	Exon 43 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5461A>G	p.Met1821Val	missense_variant	Exon 43 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000399603.6	c.5445-584A>G		intron_variant	Intron 42 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5445-584A>G		intron_variant	Intron 42 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000406454.8	c.5658-584A>G		intron_variant	Intron 43 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5625-584A>G		intron_variant	Intron 42 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5610-584A>G		intron_variant	Intron 43 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5589-584A>G		intron_variant	Intron 44 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5568-584A>G		intron_variant	Intron 42 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000682462.1	c.5535-584A>G		intron_variant	Intron 42 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5535-584A>G		intron_variant	Intron 42 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5535-584A>G		intron_variant	Intron 42 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5535-584A>G		intron_variant	Intron 42 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5529-584A>G		intron_variant	Intron 43 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5520-584A>G		intron_variant	Intron 43 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5505-584A>G		intron_variant	Intron 43 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5502-584A>G		intron_variant	Intron 42 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5502-584A>G		intron_variant	Intron 42 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5502-584A>G		intron_variant	Intron 42 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5496-584A>G		intron_variant	Intron 42 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5487-584A>G		intron_variant	Intron 42 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5469-584A>G		intron_variant	Intron 41 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5469-584A>G		intron_variant	Intron 41 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5463-584A>G		intron_variant	Intron 41 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5445-584A>G		intron_variant	Intron 42 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5445-584A>G		intron_variant	Intron 42 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5445-584A>G		intron_variant	Intron 42 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5445-584A>G		intron_variant	Intron 42 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5445-584A>G		intron_variant	Intron 42 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5436-584A>G		intron_variant	Intron 42 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5412-584A>G		intron_variant	Intron 41 of 45			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.803 AC: 121654 AN: 151560 Hom.: 48901 Cov.: 31

Gnomad AFR AF: 0.779

Gnomad AMI AF: 0.632

Gnomad AMR AF: 0.776

Gnomad ASJ AF: 0.841

Gnomad EAS AF: 0.623

Gnomad SAS AF: 0.858

Gnomad FIN AF: 0.856

Gnomad MID AF: 0.779

Gnomad NFE AF: 0.826

Gnomad OTH AF: 0.791

GnomAD3 exomes AF: 0.808 AC: 200689 AN: 248502 Hom.: 81597 AF XY: 0.812 AC XY: 109703 AN XY: 135032

Gnomad AFR exome AF: 0.784

Gnomad AMR exome AF: 0.789

Gnomad ASJ exome AF: 0.837

Gnomad EAS exome AF: 0.622

Gnomad SAS exome AF: 0.855

Gnomad FIN exome AF: 0.854

Gnomad NFE exome AF: 0.822

Gnomad OTH exome AF: 0.812

GnomAD4 exome AF: 0.822 AC: 1188724 AN: 1446592 Hom.: 490616 Cov.: 30 AF XY: 0.823 AC XY: 593161 AN XY: 720424

Gnomad4 AFR exome AF: 0.783

Gnomad4 AMR exome AF: 0.786

Gnomad4 ASJ exome AF: 0.836

Gnomad4 EAS exome AF: 0.599

Gnomad4 SAS exome AF: 0.855

Gnomad4 FIN exome AF: 0.850

Gnomad4 NFE exome AF: 0.829

Gnomad4 OTH exome AF: 0.814

GnomAD4 genome AF: 0.803 AC: 121738 AN: 151676 Hom.: 48930 Cov.: 31 AF XY: 0.804 AC XY: 59525 AN XY: 74078

Gnomad4 AFR AF: 0.779

Gnomad4 AMR AF: 0.776

Gnomad4 ASJ AF: 0.841

Gnomad4 EAS AF: 0.622

Gnomad4 SAS AF: 0.858

Gnomad4 FIN AF: 0.856

Gnomad4 NFE AF: 0.826

Gnomad4 OTH AF: 0.792

Alfa AF: 0.823 Hom.: 19526

Bravo AF: 0.796

TwinsUK AF: 0.821 AC: 3043

ALSPAC AF: 0.815 AC: 3141

ESP6500AA AF: 0.794 AC: 2489

ESP6500EA AF: 0.831 AC: 5953

ExAC AF: 0.806 AC: 97141

Asia WGS AF: 0.751 AC: 2607 AN: 3478

EpiCase AF: 0.826

EpiControl AF: 0.818

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2011	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -

Timothy syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	3.0
DANN	Benign	0.40
DEOGEN2	Benign	0.0045	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.00019	N
MetaRNN	Benign	0.0000025	T;T
MetaSVM	Benign	-0.97	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.16	N;N
REVEL	Benign	0.24
Sift	Benign	0.56	T;T
Sift4G	Benign	0.52	T;T
Vest4		0.020
ClinPred		0.000018	T
GERP RS		0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs10774053; hg19: chr12-2791132; COSMIC: COSV59768974; COSMIC: COSV59768974;