12-2679760-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000719.7(CACNA1C):c.5408G>A(p.Arg1803Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000195 in 1,587,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1803W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.61

Publications

3 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 links:

ITFG2-AS1 (HGNC:53128): (ITFG2 antisense RNA 1)

ITFG2-AS1 links:

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

CACNA1C-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1943275).

BP6

Variant 12-2679760-G-A is Benign according to our data. Variant chr12-2679760-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 219520.

BS2

High AC in GnomAdExome4 at 27 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000719.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1C	NM_000719.7	MANE Select	c.5408G>A	p.Arg1803Gln	missense	Exon 42 of 47	NP_000710.5
CACNA1C	NM_001167623.2	MANE Plus Clinical	c.5408G>A	p.Arg1803Gln	missense	Exon 42 of 47	NP_001161095.1	Q13936-37
CACNA1C	NM_199460.4		c.5552G>A	p.Arg1851Gln	missense	Exon 44 of 50	NP_955630.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1C	ENST00000399603.6	TSL:5 MANE Plus Clinical	c.5408G>A	p.Arg1803Gln	missense	Exon 42 of 47	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.5408G>A	p.Arg1803Gln	missense	Exon 42 of 47	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1		c.5642G>A	p.Arg1881Gln	missense	Exon 44 of 50	ENSP00000507184.1	A0A804HIR0

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000145

AC:

AN:

206278

AF XY:

0.00000893

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000677

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000112

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000188

AC:

AN:

1435548

Hom.:

Cov.:

AF XY:

0.0000183

AC XY:

AN XY:

711304

show subpopulations

African (AFR)

AF:

0.0000305

AC:

AN:

32756

American (AMR)

AF:

0.00

AC:

AN:

41064

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25558

East Asian (EAS)

AF:

0.000105

AC:

AN:

38158

South Asian (SAS)

AF:

0.0000121

AC:

AN:

82932

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51678

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.0000191

AC:

AN:

1098270

Other (OTH)

AF:

0.00

AC:

AN:

59408

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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:

0.0000263

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41460

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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:

0.00

Hom.:

Bravo

AF:

0.0000264

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cardiovascular phenotype (1)

Long QT syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

CardioboostArm

Benign

3.0e-7

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0093

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.087

FATHMM_MKL

Uncertain

0.92

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.19

MetaSVM

Uncertain

-0.0093

MutationAssessor

Benign

1.6

PhyloP100

2.6

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.87

REVEL

Uncertain

0.30

Sift

Benign

0.17

Sift4G

Benign

0.61

Polyphen

0.66

Vest4

0.21

MutPred

0.42

Gain of catalytic residue at L1846 (P = 8e-04)

MVP

0.65

MPC

0.22

ClinPred

0.12

GERP RS

3.0

gMVP

0.35

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over