rs576194052

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000719.7(CACNA1C):c.1669+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000849 in 1,588,314 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0017 ( 6 hom., cov: 33)

Exomes 𝑓: 0.00076 ( 9 hom. )

Consequence

CACNA1C
NM_000719.7 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.289

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 12-2566592-G-A is Benign according to our data. Variant chr12-2566592-G-A is described in ClinVar as Benign. ClinVar VariationId is 527033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00169 (257/152250) while in subpopulation EAS AF = 0.000965 (5/5182). AF 95% confidence interval is 0.00038. There are 6 homozygotes in GnomAd4. There are 195 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 257 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.1669+10G>A		intron_variant	Intron 12 of 46	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.1669+10G>A		intron_variant	Intron 12 of 46	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.1669+10G>A	intron_variant	Intron 12 of 46	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.1669+10G>A	intron_variant	Intron 12 of 46	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.1759+10G>A	intron_variant	Intron 12 of 49			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.1669+10G>A	intron_variant	Intron 12 of 47	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.1669+10G>A	intron_variant	Intron 12 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.1834+10G>A	intron_variant	Intron 13 of 47			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.1669+10G>A	intron_variant	Intron 12 of 48	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.1669+10G>A	intron_variant	Intron 12 of 46	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.1669+10G>A	intron_variant	Intron 12 of 47	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.1669+10G>A	intron_variant	Intron 12 of 47	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.1759+10G>A	intron_variant	Intron 12 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.1759+10G>A	intron_variant	Intron 12 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.1759+10G>A	intron_variant	Intron 12 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.1759+10G>A	intron_variant	Intron 12 of 46			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.1669+10G>A	intron_variant	Intron 12 of 47	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.1744+10G>A	intron_variant	Intron 13 of 47	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.1669+10G>A	intron_variant	Intron 12 of 47	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.1669+10G>A	intron_variant	Intron 12 of 46	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.1669+10G>A	intron_variant	Intron 12 of 46	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.1669+10G>A	intron_variant	Intron 12 of 46	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.1669+10G>A	intron_variant	Intron 12 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.1744+10G>A	intron_variant	Intron 13 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.1669+10G>A	intron_variant	Intron 12 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.1669+10G>A	intron_variant	Intron 12 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.1669+10G>A	intron_variant	Intron 12 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.1669+10G>A	intron_variant	Intron 12 of 46	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.1669+10G>A	intron_variant	Intron 12 of 46	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.1669+10G>A	intron_variant	Intron 12 of 46	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.1669+10G>A	intron_variant	Intron 12 of 46	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.1669+10G>A	intron_variant	Intron 12 of 46			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.1660+10G>A	intron_variant	Intron 12 of 46			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.1669+10G>A	intron_variant	Intron 12 of 45			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.*276+10G>A	intron_variant	Intron 10 of 26	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

AF:

0.00169

AC:

257

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0212

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000338

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00180

AC:

377

AN:

209888

AF XY:

0.00181

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000395

Gnomad FIN exome

AF:

0.0170

Gnomad NFE exome

AF:

0.000464

Gnomad OTH exome

AF:

0.000752

GnomAD4 exome

AF:

0.000760

AC:

1092

AN:

1436064

Hom.:

Cov.:

AF XY:

0.000770

AC XY:

548

AN XY:

711758

show subpopulations

African (AFR)

AF:

0.000122

AC:

AN:

32746

American (AMR)

AF:

0.00

AC:

AN:

42218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25634

East Asian (EAS)

AF:

0.000550

AC:

AN:

38174

South Asian (SAS)

AF:

0.0000979

AC:

AN:

81714

European-Finnish (FIN)

AF:

0.0166

AC:

853

AN:

51520

Middle Eastern (MID)

AF:

0.000200

AC:

AN:

4988

European-Non Finnish (NFE)

AF:

0.000145

AC:

160

AN:

1099786

Other (OTH)

AF:

0.000759

AC:

AN:

59284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

114

171

228

285

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00169

AC:

257

AN:

152250

Hom.:

Cov.:

AF XY:

0.00262

AC XY:

195

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41542

American (AMR)

AF:

0.0000654

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000965

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0212

AC:

225

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000338

AC:

AN:

68020

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000475

Hom.:

Bravo

AF:

0.0000982

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Oct 23, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 11, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CACNA1C-related disorder

Benign:1

Apr 26, 2019

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). -

not provided

Benign:1

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Benign:1

Jan 20, 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

0.18

(source)

DANN

Benign

0.73

PhyloP100

-0.29

PromoterAI

-0.0097

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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