rs374269485

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_000719.7(CACNA1C):c.2664-6G>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 0.0000831 in 1,612,734 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000088 ( 1 hom. )

Consequence

CACNA1C
NM_000719.7 splice_region, intron

Scores

Splicing: ADA: 0.000009096

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.139

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 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.02).

BP6

Variant 12-2595868-G-A is Benign according to our data. Variant chr12-2595868-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 456956.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.2664-6G>A		splice_region_variant, intron_variant	Intron 19 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.2664-6G>A		splice_region_variant, intron_variant	Intron 19 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.2664-6G>A	splice_region_variant, intron_variant	Intron 19 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.2664-6G>A	splice_region_variant, intron_variant	Intron 19 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.2754-6G>A	splice_region_variant, intron_variant	Intron 19 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.2664-6G>A	splice_region_variant, intron_variant	Intron 19 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.2664-6G>A	splice_region_variant, intron_variant	Intron 19 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.2829-6G>A	splice_region_variant, intron_variant	Intron 20 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.2664-6G>A	splice_region_variant, intron_variant	Intron 19 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.2664-6G>A	splice_region_variant, intron_variant	Intron 19 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.2664-6G>A	splice_region_variant, intron_variant	Intron 19 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.2664-6G>A	splice_region_variant, intron_variant	Intron 19 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.2754-6G>A	splice_region_variant, intron_variant	Intron 19 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.2754-6G>A	splice_region_variant, intron_variant	Intron 19 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.2754-6G>A	splice_region_variant, intron_variant	Intron 19 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.2754-6G>A	splice_region_variant, intron_variant	Intron 19 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.2664-6G>A	splice_region_variant, intron_variant	Intron 19 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.2739-6G>A	splice_region_variant, intron_variant	Intron 20 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.2664-6G>A	splice_region_variant, intron_variant	Intron 19 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.2664-6G>A	splice_region_variant, intron_variant	Intron 19 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.2664-6G>A	splice_region_variant, intron_variant	Intron 19 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.2664-6G>A	splice_region_variant, intron_variant	Intron 19 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.2664-6G>A	splice_region_variant, intron_variant	Intron 19 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.2739-6G>A	splice_region_variant, intron_variant	Intron 20 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.2664-6G>A	splice_region_variant, intron_variant	Intron 19 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.2664-6G>A	splice_region_variant, intron_variant	Intron 19 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.2664-6G>A	splice_region_variant, intron_variant	Intron 19 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.2664-6G>A	splice_region_variant, intron_variant	Intron 19 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.2664-6G>A	splice_region_variant, intron_variant	Intron 19 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.2664-6G>A	splice_region_variant, intron_variant	Intron 19 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.2664-6G>A	splice_region_variant, intron_variant	Intron 19 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.2664-6G>A	splice_region_variant, intron_variant	Intron 19 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.2655-6G>A	splice_region_variant, intron_variant	Intron 19 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.2664-6G>A	splice_region_variant, intron_variant	Intron 19 of 45			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.*1271-6G>A	splice_region_variant, intron_variant	Intron 17 of 26	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152076

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000378

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000149

AC:

AN:

248256

AF XY:

0.000156

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000408

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000658

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.000332

GnomAD4 exome

AF:

0.0000876

AC:

128

AN:

1460658

Hom.:

Cov.:

AF XY:

0.0000894

AC XY:

AN XY:

726668

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33464

American (AMR)

AF:

0.000358

AC:

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39644

South Asian (SAS)

AF:

0.0000813

AC:

AN:

86116

European-Finnish (FIN)

AF:

0.000528

AC:

AN:

53016

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000576

AC:

AN:

1111524

Other (OTH)

AF:

0.000116

AC:

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.0000395

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41414

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000378

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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:

0.0000512

Hom.:

Bravo

AF:

0.0000642

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Long QT syndrome

Benign:1

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely 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

-1.0

CADD

Benign

0.44

(source)

DANN

Benign

0.39

PhyloP100

0.14

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000091

dbscSNV1_RF

Benign

0.0020

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