Genetic Variant CACNA1C:p.Pro1883Pro (chr12-2685811-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000719.7(CACNA1C):c.5649G>A(p.Pro1883Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0199 in 1,556,064 control chromosomes in the GnomAD database, including 345 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1883P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.017 ( 34 hom., cov: 32)

Exomes 𝑓: 0.020 ( 311 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.308

Publications

16 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 12-2685811-G-A is Benign according to our data. Variant chr12-2685811-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.308 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0167 (2485/148444) while in subpopulation EAS AF = 0.0384 (198/5154). AF 95% confidence interval is 0.034. There are 34 homozygotes in GnomAd4. There are 1210 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2485 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.5649G>A	p.Pro1883Pro	synonymous	Exon 44 of 47	NP_000710.5
CACNA1C	NM_001167623.2	MANE Plus Clinical	c.5649G>A	p.Pro1883Pro	synonymous	Exon 44 of 47	NP_001161095.1
CACNA1C	NM_199460.4		c.5898G>A	p.Pro1966Pro	synonymous	Exon 47 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.5649G>A	p.Pro1883Pro	synonymous	Exon 44 of 47	ENSP00000382512.1
CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.5649G>A	p.Pro1883Pro	synonymous	Exon 44 of 47	ENSP00000382563.1
CACNA1C	ENST00000682544.1		c.5988G>A	p.Pro1996Pro	synonymous	Exon 47 of 50	ENSP00000507184.1

Frequencies

GnomAD3 genomes

AF:

0.0168

AC:

2488

AN:

148338

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00935

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0108

Gnomad ASJ

AF:

0.0245

Gnomad EAS

AF:

0.0385

Gnomad SAS

AF:

0.00610

Gnomad FIN

AF:

0.0268

Gnomad MID

AF:

0.0129

Gnomad NFE

AF:

0.0199

Gnomad OTH

AF:

0.0147

GnomAD2 exomes

AF:

0.0207

AC:

4973

AN:

239870

AF XY:

0.0197

show subpopulations

Gnomad AFR exome

AF:

0.0226

Gnomad AMR exome

AF:

0.00914

Gnomad ASJ exome

AF:

0.0238

Gnomad EAS exome

AF:

0.0410

Gnomad FIN exome

AF:

0.0272

Gnomad NFE exome

AF:

0.0236

Gnomad OTH exome

AF:

0.0216

GnomAD4 exome

AF:

0.0203

AC:

28550

AN:

1407620

Hom.:

311

Cov.:

AF XY:

0.0196

AC XY:

13755

AN XY:

701650

show subpopulations

African (AFR)

AF:

0.0210

AC:

642

AN:

30530

American (AMR)

AF:

0.00894

AC:

387

AN:

43266

Ashkenazi Jewish (ASJ)

AF:

0.0238

AC:

602

AN:

25332

East Asian (EAS)

AF:

0.0278

AC:

1095

AN:

39362

South Asian (SAS)

AF:

0.00479

AC:

406

AN:

84770

European-Finnish (FIN)

AF:

0.0262

AC:

1380

AN:

52734

Middle Eastern (MID)

AF:

0.0163

AC:

AN:

5538

European-Non Finnish (NFE)

AF:

0.0213

AC:

22768

AN:

1067774

Other (OTH)

AF:

0.0202

AC:

1180

AN:

58314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

1206

2412

3617

4823

6029

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

900

1800

2700

3600

4500

<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:

0.0167

AC:

2485

AN:

148444

Hom.:

Cov.:

AF XY:

0.0167

AC XY:

1210

AN XY:

72510

show subpopulations

African (AFR)

AF:

0.00932

AC:

367

AN:

39380

American (AMR)

AF:

0.0108

AC:

162

AN:

15050

Ashkenazi Jewish (ASJ)

AF:

0.0245

AC:

AN:

3430

East Asian (EAS)

AF:

0.0384

AC:

198

AN:

5154

South Asian (SAS)

AF:

0.00589

AC:

AN:

4752

European-Finnish (FIN)

AF:

0.0268

AC:

278

AN:

10376

Middle Eastern (MID)

AF:

0.0139

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.0199

AC:

1334

AN:

67050

Other (OTH)

AF:

0.0146

AC:

AN:

2054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

114

228

342

456

570

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0218

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

May 18, 2017

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 13, 2014

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Nov 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Long QT syndrome

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

Jun 26, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

3.8

(source)

DANN

Benign

0.87

PhyloP100

-0.31

Mutation Taster

=99/1

polymorphism (auto)

(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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over