chr12-2681964-C-T

Position:

chr12-2681964-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The ENST00000327702.12(CACNA1C):c.5459C>T(p.Pro1820Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 1,596,264 control chromosomes in the GnomAD database, including 511,775 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 (★★). Synonymous variant affecting the same amino acid position (i.e. P1820P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.71 ( 40081 hom., cov: 32)

Exomes 𝑓: 0.80 ( 471694 hom. )

Consequence

CACNA1C
ENST00000327702.12 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.47

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 -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1C. . Gene score misZ 6.4654 (greater than the threshold 3.09). Trascript score misZ 7.2194 (greater than threshold 3.09). GenCC has associacion of gene with 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=1.8183505E-6).

BP6

Variant 12-2681964-C-T is Benign according to our data. Variant chr12-2681964-C-T is described in ClinVar as [Benign]. Clinvar id is 136638.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2681964-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.82 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
CACNA1C	NM_000719.7 linkuse as main transcript	c.5445-586C>T	intron_variant	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 linkuse as main transcript	c.5445-586C>T	intron_variant	ENST00000399603.6	NP_001161095.1
CACNA1C-AS1	NR_045725.1 linkuse as main transcript	n.334-4067G>A	intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 linkuse as main transcript	c.5445-586C>T	intron_variant	5	NM_001167623.2	ENSP00000382512	Q13936-37
CACNA1C	ENST00000399655.6 linkuse as main transcript	c.5445-586C>T	intron_variant	1	NM_000719.7	ENSP00000382563	Q13936-12
CACNA1C-AS1	ENST00000501371.5 linkuse as main transcript	n.295-4067G>A	intron_variant, non_coding_transcript_variant	2

Frequencies

GnomAD3 genomes

AF:

0.713

AC:

107994

AN:

151514

Hom.:

40074

Cov.:

show subpopulations

Gnomad AFR

AF:

0.491

Gnomad AMI

AF:

0.631

Gnomad AMR

AF:

0.731

Gnomad ASJ

AF:

0.821

Gnomad EAS

AF:

0.594

Gnomad SAS

AF:

0.842

Gnomad FIN

AF:

0.854

Gnomad MID

AF:

0.731

Gnomad NFE

AF:

0.817

Gnomad OTH

AF:

0.711

GnomAD3 exomes

AF:

0.777

AC:

193185

AN:

248494

Hom.:

76482

AF XY:

0.787

AC XY:

106275

AN XY:

135028

show subpopulations

Gnomad AFR exome

AF:

0.485

Gnomad AMR exome

AF:

0.769

Gnomad ASJ exome

AF:

0.815

Gnomad EAS exome

AF:

0.591

Gnomad SAS exome

AF:

0.845

Gnomad FIN exome

AF:

0.852

Gnomad NFE exome

AF:

0.813

Gnomad OTH exome

AF:

0.789

GnomAD4 exome

AF:

0.804

AC:

1162010

AN:

1444634

Hom.:

471694

Cov.:

AF XY:

0.807

AC XY:

580629

AN XY:

719614

show subpopulations

Gnomad4 AFR exome

AF:

0.473

Gnomad4 AMR exome

AF:

0.764

Gnomad4 ASJ exome

AF:

0.815

Gnomad4 EAS exome

AF:

0.576

Gnomad4 SAS exome

AF:

0.843

Gnomad4 FIN exome

AF:

0.848

Gnomad4 NFE exome

AF:

0.820

Gnomad4 OTH exome

AF:

0.782

GnomAD4 genome

AF:

0.712

AC:

108036

AN:

151630

Hom.:

40081

Cov.:

AF XY:

0.716

AC XY:

53006

AN XY:

74058

show subpopulations

Gnomad4 AFR

AF:

0.491

Gnomad4 AMR

AF:

0.731

Gnomad4 ASJ

AF:

0.821

Gnomad4 EAS

AF:

0.593

Gnomad4 SAS

AF:

0.842

Gnomad4 FIN

AF:

0.854

Gnomad4 NFE

AF:

0.817

Gnomad4 OTH

AF:

0.712

Alfa

AF:

0.796

Hom.:

81034

Bravo

AF:

0.692

TwinsUK

AF:

0.814

AC:

3018

ALSPAC

AF:

0.807

AC:

3112

ESP6500AA

AF:

0.504

AC:

1581

ESP6500EA

AF:

0.821

AC:

5884

ExAC

AF:

0.772

AC:

92945

Asia WGS

AF:

0.708

AC:

2459

AN:

3478

EpiCase

AF:

0.817

EpiControl

AF:

0.807

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, 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	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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

-0.56

BayesDel_noAF

Benign

-0.43

CADD

Benign

0.16

DANN

Benign

0.54

DEOGEN2

Benign

0.014

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.00024

MetaRNN

Benign

0.0000018

T;T

MetaSVM

Benign

-0.95

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

0.28

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.19

Sift

Benign

0.24

T;T

Sift4G

Benign

0.10

T;T

Vest4

0.066

ClinPred

0.0050

GERP RS

1.6

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

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