rs761966966

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3BP6BS2

The NM_000719.7(CACNA1C):c.5098G>A(p.Gly1700Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,560,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging 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. G1700R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 9.30

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: Likely_benign. The variant received -4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.833

BP6

Variant 12-2679450-G-A is Benign according to our data. Variant chr12-2679450-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 526905.

BS2

High AC in GnomAd4 at 5 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
CACNA1C	NM_000719.7	MANE Select	c.5098G>A	p.Gly1700Ser	missense	Exon 42 of 47	NP_000710.5
CACNA1C	NM_001167623.2	MANE Plus Clinical	c.5098G>A	p.Gly1700Ser	missense	Exon 42 of 47	NP_001161095.1
CACNA1C	NM_199460.4		c.5242G>A	p.Gly1748Ser	missense	Exon 44 of 50	NP_955630.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNA1C	ENST00000399603.6	TSL:5 MANE Plus Clinical	c.5098G>A	p.Gly1700Ser	missense	Exon 42 of 47	ENSP00000382512.1
CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.5098G>A	p.Gly1700Ser	missense	Exon 42 of 47	ENSP00000382563.1
CACNA1C	ENST00000682544.1		c.5332G>A	p.Gly1778Ser	missense	Exon 44 of 50	ENSP00000507184.1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000580

AC:

AN:

189716

AF XY:

0.0000690

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000338

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000107

Gnomad OTH exome

AF:

0.000207

GnomAD4 exome

AF:

0.000132

AC:

186

AN:

1408372

Hom.:

Cov.:

AF XY:

0.000133

AC XY:

AN XY:

694264

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32386

American (AMR)

AF:

0.0000500

AC:

AN:

39974

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23214

East Asian (EAS)

AF:

0.0000525

AC:

AN:

38076

South Asian (SAS)

AF:

0.00

AC:

AN:

76928

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49928

Middle Eastern (MID)

AF:

0.000179

AC:

AN:

5574

European-Non Finnish (NFE)

AF:

0.000157

AC:

170

AN:

1084088

Other (OTH)

AF:

0.000189

AC:

AN:

58204

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

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:

0.0000329

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41452

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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:

0.000682

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000665

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Cardiovascular phenotype (1)

Long QT syndrome (1)

not specified (1)

Timothy syndrome;C2678478:Brugada syndrome 3 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

CardioboostArm

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.017

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.83

MetaSVM

Pathogenic

0.89

MutationAssessor

Pathogenic

3.0

PhyloP100

9.3

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-5.2

REVEL

Pathogenic

0.78

Sift

Uncertain

0.014

Sift4G

Benign

0.11

Polyphen

1.0

Vest4

0.86

MutPred

0.57

Gain of catalytic residue at N1753 (P = 0.001)

MVP

0.97

MPC

0.34

ClinPred

0.61

GERP RS

4.4

gMVP

0.67

Mutation Taster

=38/62

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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