rs1544515

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000719.7(CACNA1C):c.617+17G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,503,642 control chromosomes in the GnomAD database, including 48,977 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.27 ( 5594 hom., cov: 32)

Exomes 𝑓: 0.25 ( 43383 hom. )

Consequence

CACNA1C
NM_000719.7 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.741

Publications

11 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:

ENSG00000285734 (HGNC:):

ENSG00000285734 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 12-2449132-G-A is Benign according to our data. Variant chr12-2449132-G-A is described in ClinVar as Benign. ClinVar VariationId is 93420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.617+17G>A		intron_variant	Intron 4 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.617+17G>A		intron_variant	Intron 4 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.617+17G>A	intron_variant	Intron 4 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.617+17G>A	intron_variant	Intron 4 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.707+17G>A	intron_variant	Intron 4 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.617+17G>A	intron_variant	Intron 4 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.617+17G>A	intron_variant	Intron 4 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.707+17G>A	intron_variant	Intron 4 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.617+17G>A	intron_variant	Intron 4 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.617+17G>A	intron_variant	Intron 4 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.617+17G>A	intron_variant	Intron 4 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.617+17G>A	intron_variant	Intron 4 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.707+17G>A	intron_variant	Intron 4 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.707+17G>A	intron_variant	Intron 4 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.707+17G>A	intron_variant	Intron 4 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.707+17G>A	intron_variant	Intron 4 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.617+17G>A	intron_variant	Intron 4 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.617+17G>A	intron_variant	Intron 4 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.617+17G>A	intron_variant	Intron 4 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.617+17G>A	intron_variant	Intron 4 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.617+17G>A	intron_variant	Intron 4 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.617+17G>A	intron_variant	Intron 4 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.617+17G>A	intron_variant	Intron 4 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.617+17G>A	intron_variant	Intron 4 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.617+17G>A	intron_variant	Intron 4 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.617+17G>A	intron_variant	Intron 4 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.617+17G>A	intron_variant	Intron 4 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.617+17G>A	intron_variant	Intron 4 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.617+17G>A	intron_variant	Intron 4 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.617+17G>A	intron_variant	Intron 4 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.617+17G>A	intron_variant	Intron 4 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.617+17G>A	intron_variant	Intron 4 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.617+17G>A	intron_variant	Intron 4 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.617+17G>A	intron_variant	Intron 4 of 45			ENSP00000507309.1
CACNA1C	ENST00000682152.1 link	c.566+17G>A	intron_variant	Intron 3 of 5			ENSP00000506759.1
CACNA1C	ENST00000480911.6 link	n.617+17G>A	intron_variant	Intron 4 of 26	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

AF:

0.269

AC:

40815

AN:

151714

Hom.:

5583

Cov.:

show subpopulations

Gnomad AFR

AF:

0.322

Gnomad AMI

AF:

0.342

Gnomad AMR

AF:

0.228

Gnomad ASJ

AF:

0.323

Gnomad EAS

AF:

0.177

Gnomad SAS

AF:

0.304

Gnomad FIN

AF:

0.247

Gnomad MID

AF:

0.228

Gnomad NFE

AF:

0.251

Gnomad OTH

AF:

0.249

GnomAD2 exomes

AF:

0.251

AC:

34268

AN:

136684

AF XY:

0.254

show subpopulations

Gnomad AFR exome

AF:

0.330

Gnomad AMR exome

AF:

0.190

Gnomad ASJ exome

AF:

0.313

Gnomad EAS exome

AF:

0.179

Gnomad FIN exome

AF:

0.242

Gnomad NFE exome

AF:

0.249

Gnomad OTH exome

AF:

0.258

GnomAD4 exome

AF:

0.250

AC:

338422

AN:

1351810

Hom.:

43383

Cov.:

AF XY:

0.252

AC XY:

167424

AN XY:

663532

show subpopulations

African (AFR)

AF:

0.329

AC:

9774

AN:

29724

American (AMR)

AF:

0.187

AC:

5454

AN:

29156

Ashkenazi Jewish (ASJ)

AF:

0.313

AC:

7420

AN:

23744

East Asian (EAS)

AF:

0.205

AC:

7213

AN:

35242

South Asian (SAS)

AF:

0.293

AC:

20798

AN:

71040

European-Finnish (FIN)

AF:

0.243

AC:

11863

AN:

48868

Middle Eastern (MID)

AF:

0.254

AC:

1395

AN:

5492

European-Non Finnish (NFE)

AF:

0.247

AC:

260347

AN:

1052390

Other (OTH)

AF:

0.252

AC:

14158

AN:

56154

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

10292

20584

30877

41169

51461

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9128

18256

27384

36512

45640

<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:

0.269

AC:

40875

AN:

151832

Hom.:

5594

Cov.:

AF XY:

0.269

AC XY:

19936

AN XY:

74190

show subpopulations

African (AFR)

AF:

0.322

AC:

13299

AN:

41342

American (AMR)

AF:

0.228

AC:

3477

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.323

AC:

1121

AN:

3468

East Asian (EAS)

AF:

0.177

AC:

915

AN:

5172

South Asian (SAS)

AF:

0.305

AC:

1470

AN:

4812

European-Finnish (FIN)

AF:

0.247

AC:

2607

AN:

10550

Middle Eastern (MID)

AF:

0.235

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.251

AC:

17073

AN:

67920

Other (OTH)

AF:

0.254

AC:

533

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1523

3045

4568

6090

7613

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

428

856

1284

1712

2140

<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:

0.259

Hom.:

4718

Bravo

AF:

0.270

Asia WGS

AF:

0.300

AC:

1041

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 23, 2013

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 10, 2011

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: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

- -

Timothy syndrome

Benign:1

Jul 14, 2021

Genome-Nilou Lab

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.16

(source)

DANN

Benign

0.51

PhyloP100

-0.74

Mutation Taster

=100/0

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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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