rs781306162

Positions:

chr12-2566562-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 3P and 14B. PM1PP2BP4_ModerateBP6_Very_StrongBS2

The ENST00000399655.6(CACNA1C):c.1649A>G(p.Asn550Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000388 in 1,598,624 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

CACNA1C
ENST00000399655.6 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.25

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a repeat II (size 246) in uniprot entity CAC1C_HUMAN there are 25 pathogenic changes around while only 10 benign (71%) in ENST00000399655.6

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=0.1659621).

BP6

Variant 12-2566562-A-G is Benign according to our data. Variant chr12-2566562-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 575658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 59 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7 linkuse as main transcript	c.1649A>G	p.Asn550Ser	missense_variant	12/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 linkuse as main transcript	c.1649A>G	p.Asn550Ser	missense_variant	12/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6 linkuse as main transcript	c.1649A>G	p.Asn550Ser	missense_variant	12/47	5	NM_001167623.2	ENSP00000382512		Q13936-37
CACNA1C	ENST00000399655.6 linkuse as main transcript	c.1649A>G	p.Asn550Ser	missense_variant	12/47	1	NM_000719.7	ENSP00000382563		Q13936-12

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000178

AC:

AN:

224750

Hom.:

AF XY:

0.0000165

AC XY:

AN XY:

121332

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000618

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000610

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000990

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000408

AC:

AN:

1446438

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

717842

show subpopulations

Gnomad4 AFR exome

AF:

0.0000302

Gnomad4 AMR exome

AF:

0.0000232

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000498

Gnomad4 OTH exome

AF:

0.0000334

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000740

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 18, 2023

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 08, 2022

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

-0.18

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.37

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

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.011

FATHMM_MKL

Pathogenic

0.98

M_CAP

Benign

0.070

MetaRNN

Benign

0.17

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

-0.17

MutationAssessor

Benign

0.43

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

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.88

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.48

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

Sift4G

Benign

0.53

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

Polyphen

0.0, 0.0010, 0.018

.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;B

Vest4

0.14

MutPred

0.35

.;Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);Gain of catalytic residue at N547 (P = 0.013);

MVP

0.70

MPC

0.85

ClinPred

0.13

GERP RS

4.8

gMVP

0.42

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