12-2681966-A-G

Position:

chr12-2681966-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000399655.6(CACNA1C):c.5445-584A>G variant causes a intron 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. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.80 ( 48930 hom., cov: 31)

Exomes 𝑓: 0.82 ( 490616 hom. )

Consequence

CACNA1C
ENST00000399655.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.521

Variant links:

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 links:

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

CACNA1C-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

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	Effect	MANE	Protein
CACNA1C	NM_000719.7 linkuse as main transcript	c.5445-584A>G	intron_variant	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 linkuse as main transcript	c.5445-584A>G	intron_variant	ENST00000399603.6	NP_001161095.1
CACNA1C-AS1	NR_045725.1 linkuse as main transcript	n.334-4069T>C	intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 linkuse as main transcript	c.5445-584A>G	intron_variant	5	NM_001167623.2	ENSP00000382512	Q13936-37
CACNA1C	ENST00000399655.6 linkuse as main transcript	c.5445-584A>G	intron_variant	1	NM_000719.7	ENSP00000382563	Q13936-12
CACNA1C-AS1	ENST00000501371.5 linkuse as main transcript	n.295-4069T>C	intron_variant, non_coding_transcript_variant	2

Frequencies

GnomAD3 genomes

AF:

0.803

AC:

121654

AN:

151560

Hom.:

48901

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.823

AC XY:

593161

AN XY:

720424

show subpopulations

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.:

AF XY:

0.804

AC XY:

59525

AN XY:

74078

show subpopulations

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

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
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	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. -

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

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

MetaRNN

Benign

0.0000025

T;T

MetaSVM

Benign

-0.97

MutationTaster

Benign

1.0

P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P

PrimateAI

Benign

0.37

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over