12-2688442-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000719.7(CACNA1C):c.5785-5C>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 0.0000242 in 1,613,556 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 splice_region, intron

Scores

Splicing: ADA: 0.0002164

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0960

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:

ITFG2-AS1 (HGNC:53128): (ITFG2 antisense RNA 1)

ITFG2-AS1 links:

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

CACNA1C-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 12-2688442-C-T is Benign according to our data. Variant chr12-2688442-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 456984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.5785-5C>T		splice_region_variant, intron_variant	Intron 45 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.5785-5C>T		splice_region_variant, intron_variant	Intron 45 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.5785-5C>T	splice_region_variant, intron_variant	Intron 45 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.5785-5C>T	splice_region_variant, intron_variant	Intron 45 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.6124-5C>T	splice_region_variant, intron_variant	Intron 48 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.5998-5C>T	splice_region_variant, intron_variant	Intron 46 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.5965-5C>T	splice_region_variant, intron_variant	Intron 45 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.5950-5C>T	splice_region_variant, intron_variant	Intron 46 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.5929-5C>T	splice_region_variant, intron_variant	Intron 47 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.5908-5C>T	splice_region_variant, intron_variant	Intron 45 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.5890-5C>T	splice_region_variant, intron_variant	Intron 46 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.5890-5C>T	splice_region_variant, intron_variant	Intron 46 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.5875-5C>T	splice_region_variant, intron_variant	Intron 45 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.5875-5C>T	splice_region_variant, intron_variant	Intron 45 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.5875-5C>T	splice_region_variant, intron_variant	Intron 45 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.5875-5C>T	splice_region_variant, intron_variant	Intron 45 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.5869-5C>T	splice_region_variant, intron_variant	Intron 46 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.5860-5C>T	splice_region_variant, intron_variant	Intron 46 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.5845-5C>T	splice_region_variant, intron_variant	Intron 46 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.5842-5C>T	splice_region_variant, intron_variant	Intron 45 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.5842-5C>T	splice_region_variant, intron_variant	Intron 45 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.5842-5C>T	splice_region_variant, intron_variant	Intron 45 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.5836-5C>T	splice_region_variant, intron_variant	Intron 45 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.5827-5C>T	splice_region_variant, intron_variant	Intron 45 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.5809-5C>T	splice_region_variant, intron_variant	Intron 44 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.5809-5C>T	splice_region_variant, intron_variant	Intron 44 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.5803-5C>T	splice_region_variant, intron_variant	Intron 44 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.5785-5C>T	splice_region_variant, intron_variant	Intron 45 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.5785-5C>T	splice_region_variant, intron_variant	Intron 45 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.5785-5C>T	splice_region_variant, intron_variant	Intron 45 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.5785-5C>T	splice_region_variant, intron_variant	Intron 45 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.5785-5C>T	splice_region_variant, intron_variant	Intron 45 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.5776-5C>T	splice_region_variant, intron_variant	Intron 45 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.5752-5C>T	splice_region_variant, intron_variant	Intron 44 of 45			ENSP00000507309.1

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000325

AC:

AN:

246240

AF XY:

0.0000299

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000907

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461354

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727002

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.000112

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53208

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

1111730

Other (OTH)

AF:

0.0000166

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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:

0.0000526

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41448

American (AMR)

AF:

0.000327

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

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:

0.0000712

Hom.:

Bravo

AF:

0.0000718

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

CACNA1C-related disorder

Benign:1

Feb 10, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Long QT syndrome

Benign:1

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jan 27, 2022

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

-0.60

CADD

Benign

(source)

DANN

Benign

0.77

PhyloP100

0.096

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00022

dbscSNV1_RF

Benign

0.064

SpliceAI score (max)

0.070

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