rs147896322

Positions:

chr12-2679471-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 1P and 18B. PP2BP4_ModerateBP6_Very_StrongBS1BS2

The NM_000719.7(CACNA1C):c.5119G>A(p.Val1707Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000212 in 1,591,000 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 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00021 ( 1 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 9.30

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 -17 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 7.2674 (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=0.15100849).

BP6

Variant 12-2679471-G-A is Benign according to our data. Variant chr12-2679471-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 190621.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-2679471-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000215 (309/1438778) while in subpopulation MID AF= 0.00511 (29/5670). AF 95% confidence interval is 0.00366. There are 1 homozygotes in gnomad4_exome. There are 176 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CACNA1C	NM_000719.7 linkuse as main transcript	c.5119G>A	p.Val1707Ile	missense_variant	42/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 linkuse as main transcript	c.5119G>A	p.Val1707Ile	missense_variant	42/47	ENST00000399603.6	NP_001161095.1
CACNA1C-AS1	NR_045725.1 linkuse as main transcript	n.334-1574C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 linkuse as main transcript	c.5119G>A	p.Val1707Ile	missense_variant	42/47	5	NM_001167623.2	ENSP00000382512	Q13936-37
CACNA1C	ENST00000399655.6 linkuse as main transcript	c.5119G>A	p.Val1707Ile	missense_variant	42/47	1	NM_000719.7	ENSP00000382563	Q13936-12
CACNA1C-AS1	ENST00000501371.5 linkuse as main transcript	n.295-1574C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000267

AC:

AN:

224776

Hom.:

AF XY:

0.000312

AC XY:

AN XY:

121698

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000245

Gnomad ASJ exome

AF:

0.000232

Gnomad EAS exome

AF:

0.000118

Gnomad SAS exome

AF:

0.000337

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000355

Gnomad OTH exome

AF:

0.000540

GnomAD4 exome

AF:

0.000215

AC:

309

AN:

1438778

Hom.:

Cov.:

AF XY:

0.000247

AC XY:

176

AN XY:

712844

show subpopulations

Gnomad4 AFR exome

AF:

0.0000606

Gnomad4 AMR exome

AF:

0.000233

Gnomad4 ASJ exome

AF:

0.0000804

Gnomad4 EAS exome

AF:

0.0000768

Gnomad4 SAS exome

AF:

0.000387

Gnomad4 FIN exome

AF:

0.0000192

Gnomad4 NFE exome

AF:

0.000188

Gnomad4 OTH exome

AF:

0.000387

GnomAD4 genome

AF:

0.000184

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000227

Hom.:

Bravo

AF:

0.000227

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.000298

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	CACNA1C: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 23, 2018

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. -

Long QT syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 10, 2019

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_addAF

Benign

0.0087

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0047

T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.15

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.50

MutationAssessor

Uncertain

2.3

.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.59

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.

REVEL

Uncertain

0.50

Sift

Benign

0.15

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.

Sift4G

Benign

0.56

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

1.0, 0.33, 0.33, 0.14, 1.0, 0.35, 1.0, 0.99

.;D;B;B;B;D;D;D;B;D;D;D;D;D;D;.;D;D;.;.;.;D;.

Vest4

0.66

MVP

0.85

MPC

0.43

ClinPred

0.093

GERP RS

4.4

gMVP

0.44

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