chr12-2606981-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_000719.7(CACNA1C):c.3210-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,568 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 splice_region, intron

Scores

Splicing: ADA: 0.9513

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.97

Publications

0 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:

CACNA1C-AS3 (HGNC:40117): (CACNA1C antisense RNA 3)

CACNA1C-AS3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.17).

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.3210-3C>T		splice_region_variant, intron_variant	Intron 25 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.3210-3C>T		splice_region_variant, intron_variant	Intron 25 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.3210-3C>T	splice_region_variant, intron_variant	Intron 25 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.3210-3C>T	splice_region_variant, intron_variant	Intron 25 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.3360-3C>T	splice_region_variant, intron_variant	Intron 26 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.3210-3C>T	splice_region_variant, intron_variant	Intron 25 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.3210-3C>T	splice_region_variant, intron_variant	Intron 25 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.3375-3C>T	splice_region_variant, intron_variant	Intron 26 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.3270-3C>T	splice_region_variant, intron_variant	Intron 26 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.3210-3C>T	splice_region_variant, intron_variant	Intron 25 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.3210-3C>T	splice_region_variant, intron_variant	Intron 25 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.3210-3C>T	splice_region_variant, intron_variant	Intron 25 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.3300-3C>T	splice_region_variant, intron_variant	Intron 25 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.3300-3C>T	splice_region_variant, intron_variant	Intron 25 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.3300-3C>T	splice_region_variant, intron_variant	Intron 25 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.3300-3C>T	splice_region_variant, intron_variant	Intron 25 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.3210-3C>T	splice_region_variant, intron_variant	Intron 25 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.3285-3C>T	splice_region_variant, intron_variant	Intron 26 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.3270-3C>T	splice_region_variant, intron_variant	Intron 26 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.3210-3C>T	splice_region_variant, intron_variant	Intron 25 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.3210-3C>T	splice_region_variant, intron_variant	Intron 25 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.3210-3C>T	splice_region_variant, intron_variant	Intron 25 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.3210-3C>T	splice_region_variant, intron_variant	Intron 25 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.3285-3C>T	splice_region_variant, intron_variant	Intron 26 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.3210-3C>T	splice_region_variant, intron_variant	Intron 25 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.3210-3C>T	splice_region_variant, intron_variant	Intron 25 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.3210-3C>T	splice_region_variant, intron_variant	Intron 25 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.3210-3C>T	splice_region_variant, intron_variant	Intron 25 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.3210-3C>T	splice_region_variant, intron_variant	Intron 25 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.3210-3C>T	splice_region_variant, intron_variant	Intron 25 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.3210-3C>T	splice_region_variant, intron_variant	Intron 25 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.3210-3C>T	splice_region_variant, intron_variant	Intron 25 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.3201-3C>T	splice_region_variant, intron_variant	Intron 25 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.3210-3C>T	splice_region_variant, intron_variant	Intron 25 of 45			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.*1817-3C>T	splice_region_variant, intron_variant	Intron 23 of 26	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000402

AC:

AN:

249026

AF XY:

0.0000444

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000556

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461364

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726922

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.000151

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111586

Other (OTH)

AF:

0.00

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000385

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.00

Hom.:

Bravo

AF:

0.0000151

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:1

Aug 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 25 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 (rs750874261, gnomAD 0.05%). 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: 568276). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

2.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.95

dbscSNV1_RF

Benign

0.30

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