12-2486244-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_000719.7(CACNA1C):c.898A>G(p.Asn300Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000688 in 1,613,330 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000070 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.562

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

Timothy syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
long QT syndrome
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
long QT syndrome 8
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
Brugada syndrome
Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen
Brugada syndrome 3
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
short QT syndrome
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen

CACNA1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 12-2486244-A-G is Benign according to our data. Variant chr12-2486244-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 457002.

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.988A>G	p.Asn330Asp	missense_variant	Exon 6 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.988A>G	p.Asn330Asp	missense_variant	Exon 6 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.988A>G	p.Asn330Asp	missense_variant	Exon 6 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.988A>G	p.Asn330Asp	missense_variant	Exon 6 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.988A>G	p.Asn330Asp	missense_variant	Exon 6 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.988A>G	p.Asn330Asp	missense_variant	Exon 6 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.898A>G	p.Asn300Asp	missense_variant	Exon 6 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1 link	c.847A>G	p.Asn283Asp	missense_variant	Exon 5 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6 link	n.898A>G		non_coding_transcript_exon_variant	Exon 6 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000241

AC:

AN:

248554

AF XY:

0.0000445

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000581

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000355

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000698

AC:

102

AN:

1461272

Hom.:

Cov.:

AF XY:

0.0000702

AC XY:

AN XY:

726910

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33470

American (AMR)

AF:

0.0000671

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86160

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000873

AC:

AN:

1111624

Other (OTH)

AF:

0.0000166

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152058

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41392

American (AMR)

AF:

0.000131

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000464

Hom.:

Bravo

AF:

0.0000491

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8

Uncertain:1

Oct 02, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Benign:1

Apr 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jul 05, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

AlphaMissense

Benign

0.13

CardioboostArm

Benign

0.066

BayesDel_addAF

Benign

-0.091

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

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

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.091

FATHMM_MKL

Uncertain

0.91

M_CAP

Pathogenic

0.65

MetaRNN

Uncertain

0.62

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

MetaSVM

Uncertain

0.11

MutationAssessor

Benign

-0.63

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

PhyloP100

0.56

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.7

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

REVEL

Pathogenic

0.77

Sift

Benign

0.47

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

0.34

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

Polyphen

0.14, 0.0010, 0.0, 0.066, 0.099, 0.27, 0.21, 0.94, 0.59

.;B;.;B;B;B;B;B;B;B;B;B;B;B;P;B;.;B;B;.;.;.;P

Vest4

0.64

MVP

0.77

MPC

1.2

ClinPred

0.23

GERP RS

5.0

gMVP

0.94

Mutation Taster

=0/100

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over