Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000719.7(CACNA1C):c.4038C>T(p.Ile1346Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.058 in 1,613,286 control chromosomes in the GnomAD database, including 3,153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.045 ( 205 hom., cov: 31)

Exomes 𝑓: 0.059 ( 2948 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.16

Publications

13 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: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.25).

BP6

Variant 12-2651732-C-T is Benign according to our data. Variant chr12-2651732-C-T is described in ClinVar as Benign. ClinVar VariationId is 136623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=3.16 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0644 is higher than 0.05.

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.4038C>T	p.Ile1346Ile	synonymous	Exon 32 of 47	NP_000710.5
CACNA1C	NM_001167623.2	MANE Plus Clinical	c.4038C>T	p.Ile1346Ile	synonymous	Exon 32 of 47	NP_001161095.1
CACNA1C	NM_199460.4		c.4182C>T	p.Ile1394Ile	synonymous	Exon 34 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.4038C>T	p.Ile1346Ile	synonymous	Exon 32 of 47	ENSP00000382512.1
CACNA1C	ENST00000399655.6	TSL:1 MANE Select	c.4038C>T	p.Ile1346Ile	synonymous	Exon 32 of 47	ENSP00000382563.1
CACNA1C	ENST00000682544.1		c.4272C>T	p.Ile1424Ile	synonymous	Exon 34 of 50	ENSP00000507184.1

Frequencies

GnomAD3 genomes

AF:

0.0447

AC:

6792

AN:

152058

Hom.:

205

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0111

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0378

Gnomad ASJ

AF:

0.0545

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.0152

Gnomad FIN

AF:

0.0807

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0660

Gnomad OTH

AF:

0.0484

GnomAD2 exomes

AF:

0.0477

AC:

11844

AN:

248480

AF XY:

0.0486

show subpopulations

Gnomad AFR exome

AF:

0.0112

Gnomad AMR exome

AF:

0.0277

Gnomad ASJ exome

AF:

0.0505

Gnomad EAS exome

AF:

0.000222

Gnomad FIN exome

AF:

0.0826

Gnomad NFE exome

AF:

0.0672

Gnomad OTH exome

AF:

0.0542

GnomAD4 exome

AF:

0.0594

AC:

86756

AN:

1461110

Hom.:

2948

Cov.:

AF XY:

0.0583

AC XY:

42369

AN XY:

726786

show subpopulations

African (AFR)

AF:

0.00854

AC:

286

AN:

33474

American (AMR)

AF:

0.0298

AC:

1331

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.0510

AC:

1332

AN:

26104

East Asian (EAS)

AF:

0.000202

AC:

AN:

39696

South Asian (SAS)

AF:

0.0186

AC:

1603

AN:

86216

European-Finnish (FIN)

AF:

0.0859

AC:

4582

AN:

53346

Middle Eastern (MID)

AF:

0.0265

AC:

153

AN:

5764

European-Non Finnish (NFE)

AF:

0.0668

AC:

74241

AN:

1111472

Other (OTH)

AF:

0.0534

AC:

3220

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

4220

8440

12660

16880

21100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2678

5356

8034

10712

13390

<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:

0.0446

AC:

6792

AN:

152176

Hom.:

205

Cov.:

AF XY:

0.0445

AC XY:

3314

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.0111

AC:

460

AN:

41536

American (AMR)

AF:

0.0377

AC:

577

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0545

AC:

189

AN:

3470

East Asian (EAS)

AF:

0.000581

AC:

AN:

5160

South Asian (SAS)

AF:

0.0154

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.0807

AC:

856

AN:

10606

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0660

AC:

4485

AN:

67988

Other (OTH)

AF:

0.0479

AC:

101

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

332

664

996

1328

1660

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

234

312

390

<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:

0.0545

Hom.:

187

Bravo

AF:

0.0394

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.0644

EpiControl

AF:

0.0662

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Cardiovascular phenotype (1)

Long QT syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.85

PhyloP100

3.2

Mutation Taster

=89/11

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

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rs56180838

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over