rs111442547

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_000719.7(CACNA1C):c.4140+4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000224 in 1,613,318 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 splice_region, intron

Scores

Splicing: ADA: 0.0002503

Clinical Significance

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

Conservation

PhyloP100: 1.23

Publications

2 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33).

BP6

Variant 12-2653904-G-A is Benign according to our data. Variant chr12-2653904-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166772.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000171 (26/152114) while in subpopulation AMR AF = 0.000655 (10/15276). AF 95% confidence interval is 0.000354. There are 0 homozygotes in GnomAd4. There are 14 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.4140+4G>A		splice_region_variant, intron_variant	Intron 33 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.4140+4G>A		splice_region_variant, intron_variant	Intron 33 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.4140+4G>A	splice_region_variant, intron_variant	Intron 33 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.4140+4G>A	splice_region_variant, intron_variant	Intron 33 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.4374+4G>A	splice_region_variant, intron_variant	Intron 35 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.4140+4G>A	splice_region_variant, intron_variant	Intron 33 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.4107+4G>A	splice_region_variant, intron_variant	Intron 32 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.4305+4G>A	splice_region_variant, intron_variant	Intron 34 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.4284+4G>A	splice_region_variant, intron_variant	Intron 35 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.4206+4G>A	splice_region_variant, intron_variant	Intron 33 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.4140+4G>A	splice_region_variant, intron_variant	Intron 33 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.4140+4G>A	splice_region_variant, intron_variant	Intron 33 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.4230+4G>A	splice_region_variant, intron_variant	Intron 33 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.4230+4G>A	splice_region_variant, intron_variant	Intron 33 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.4230+4G>A	splice_region_variant, intron_variant	Intron 33 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.4230+4G>A	splice_region_variant, intron_variant	Intron 33 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.4224+4G>A	splice_region_variant, intron_variant	Intron 34 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.4215+4G>A	splice_region_variant, intron_variant	Intron 34 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.4200+4G>A	splice_region_variant, intron_variant	Intron 34 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.4140+4G>A	splice_region_variant, intron_variant	Intron 33 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.4140+4G>A	splice_region_variant, intron_variant	Intron 33 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.4140+4G>A	splice_region_variant, intron_variant	Intron 33 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.4191+4G>A	splice_region_variant, intron_variant	Intron 33 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.4182+4G>A	splice_region_variant, intron_variant	Intron 33 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.4107+4G>A	splice_region_variant, intron_variant	Intron 32 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.4107+4G>A	splice_region_variant, intron_variant	Intron 32 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.4101+4G>A	splice_region_variant, intron_variant	Intron 32 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.4140+4G>A	splice_region_variant, intron_variant	Intron 33 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.4140+4G>A	splice_region_variant, intron_variant	Intron 33 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.4140+4G>A	splice_region_variant, intron_variant	Intron 33 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.4140+4G>A	splice_region_variant, intron_variant	Intron 33 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.4140+4G>A	splice_region_variant, intron_variant	Intron 33 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.4131+4G>A	splice_region_variant, intron_variant	Intron 33 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.4107+4G>A	splice_region_variant, intron_variant	Intron 32 of 45			ENSP00000507309.1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000109

AC:

AN:

248392

AF XY:

0.000119

show subpopulations

Gnomad AFR exome

AF:

0.0000647

Gnomad AMR exome

AF:

0.0000870

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000204

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000230

AC:

336

AN:

1461204

Hom.:

Cov.:

AF XY:

0.000227

AC XY:

165

AN XY:

726892

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33472

American (AMR)

AF:

0.000134

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53238

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000285

AC:

317

AN:

1111572

Other (OTH)

AF:

0.000166

AC:

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000171

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41408

American (AMR)

AF:

0.000655

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68022

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.000232

Hom.:

Bravo

AF:

0.000136

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Uncertain:1

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 33 of the CACNA1C gene. It does not directly change the encoded amino acid sequence of the CACNA1C protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs111442547, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 166772). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Benign:1

Dec 27, 2017

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.92

PhyloP100

1.2

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00025

dbscSNV1_RF

Benign

0.034

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over