12-2504550-C-T

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.1114-292C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0782 in 1,483,106 control chromosomes in the GnomAD database, including 4,849 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.068 ( 429 hom., cov: 32)

Exomes 𝑓: 0.079 ( 4420 hom. )

Consequence

CACNA1C
NM_000719.7 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.556

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:

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=-0.81).

BP6

Variant 12-2504550-C-T is Benign according to our data. Variant chr12-2504550-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.1114-292C>T		intron_variant	Intron 7 of 46	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.1217+11C>T		intron_variant	Intron 8 of 46	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399603.6 link	c.1217+11C>T	intron_variant	Intron 8 of 46	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000399655.6 link	c.1114-292C>T	intron_variant	Intron 7 of 46	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.1204-292C>T	intron_variant	Intron 7 of 49			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000406454.8 link	c.1217+11C>T	intron_variant	Intron 8 of 47	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.1217+11C>T	intron_variant	Intron 8 of 46	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.1307+11C>T	intron_variant	Intron 8 of 47			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000347598.9 link	c.1114-292C>T	intron_variant	Intron 7 of 48	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.1114-292C>T	intron_variant	Intron 7 of 46	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.1114-292C>T	intron_variant	Intron 7 of 47	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399617.6 link	c.1217+11C>T	intron_variant	Intron 8 of 47	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.1307+11C>T	intron_variant	Intron 8 of 46			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.1307+11C>T	intron_variant	Intron 8 of 46			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.1307+11C>T	intron_variant	Intron 8 of 46			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.1307+11C>T	intron_variant	Intron 8 of 46			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399638.5 link	c.1114-292C>T	intron_variant	Intron 7 of 47	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.1114-292C>T	intron_variant	Intron 7 of 47	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.1114-292C>T	intron_variant	Intron 7 of 47	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.1114-292C>T	intron_variant	Intron 7 of 46	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.1114-292C>T	intron_variant	Intron 7 of 46	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.1114-292C>T	intron_variant	Intron 7 of 46	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.1114-292C>T	intron_variant	Intron 7 of 46	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.1114-292C>T	intron_variant	Intron 7 of 46			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.1114-292C>T	intron_variant	Intron 7 of 45	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.1114-292C>T	intron_variant	Intron 7 of 45	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.1114-292C>T	intron_variant	Intron 7 of 45	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.1114-292C>T	intron_variant	Intron 7 of 46	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.1114-292C>T	intron_variant	Intron 7 of 46	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399641.6 link	c.1217+11C>T	intron_variant	Intron 8 of 46	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000399644.5 link	c.1114-292C>T	intron_variant	Intron 7 of 46	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000682835.1 link	c.1217+11C>T	intron_variant	Intron 8 of 46			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000683482.1 link	c.1105-292C>T	intron_variant	Intron 7 of 46			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.1114-292C>T	intron_variant	Intron 7 of 45			ENSP00000507309.1	Q13936-19
CACNA1C	ENST00000480911.6 link	n.1113+11164C>T	intron_variant	Intron 7 of 26	5		ENSP00000437936.2	F5H638

Frequencies

GnomAD3 genomes

AF:

0.0683

AC:

10362

AN:

151768

Hom.:

428

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0406

Gnomad AMI

AF:

0.0374

Gnomad AMR

AF:

0.0724

Gnomad ASJ

AF:

0.124

Gnomad EAS

AF:

0.135

Gnomad SAS

AF:

0.0790

Gnomad FIN

AF:

0.0412

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.0795

Gnomad OTH

AF:

0.0841

GnomAD2 exomes

AF:

0.0760

AC:

18888

AN:

248548

AF XY:

0.0784

show subpopulations

Gnomad AFR exome

AF:

0.0415

Gnomad AMR exome

AF:

0.0506

Gnomad ASJ exome

AF:

0.120

Gnomad EAS exome

AF:

0.139

Gnomad FIN exome

AF:

0.0402

Gnomad NFE exome

AF:

0.0818

Gnomad OTH exome

AF:

0.0796

GnomAD4 exome

AF:

0.0794

AC:

105691

AN:

1331220

Hom.:

4420

Cov.:

AF XY:

0.0798

AC XY:

53465

AN XY:

669722

show subpopulations

African (AFR)

AF:

0.0407

AC:

1259

AN:

30954

American (AMR)

AF:

0.0539

AC:

2400

AN:

44524

Ashkenazi Jewish (ASJ)

AF:

0.127

AC:

3235

AN:

25386

East Asian (EAS)

AF:

0.125

AC:

4886

AN:

39066

South Asian (SAS)

AF:

0.0747

AC:

6250

AN:

83676

European-Finnish (FIN)

AF:

0.0420

AC:

2235

AN:

53226

Middle Eastern (MID)

AF:

0.0898

AC:

494

AN:

5504

European-Non Finnish (NFE)

AF:

0.0807

AC:

80116

AN:

992780

Other (OTH)

AF:

0.0858

AC:

4816

AN:

56104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

4907

9814

14720

19627

24534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2846

5692

8538

11384

14230

<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:

0.0682

AC:

10362

AN:

151886

Hom.:

429

Cov.:

AF XY:

0.0672

AC XY:

4987

AN XY:

74218

show subpopulations

African (AFR)

AF:

0.0408

AC:

1690

AN:

41410

American (AMR)

AF:

0.0722

AC:

1101

AN:

15244

Ashkenazi Jewish (ASJ)

AF:

0.124

AC:

431

AN:

3468

East Asian (EAS)

AF:

0.135

AC:

696

AN:

5162

South Asian (SAS)

AF:

0.0782

AC:

375

AN:

4794

European-Finnish (FIN)

AF:

0.0412

AC:

435

AN:

10564

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0795

AC:

5400

AN:

67936

Other (OTH)

AF:

0.0827

AC:

174

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

486

972

1458

1944

2430

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

118

236

354

472

590

<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:

0.0796

Hom.:

1556

Bravo

AF:

0.0713

Asia WGS

AF:

0.0910

AC:

315

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 22, 2013

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:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

-0.81

CADD

Benign

9.9

(source)

DANN

Benign

0.91

PhyloP100

-0.56

PromoterAI

0.0034

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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