chr12-2582938-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_000719.7(CACNA1C):c.2220A>G(p.Gly740Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,566,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000092 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.99

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: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 12-2582938-A-G is Benign according to our data. Variant chr12-2582938-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 456952.

BS2

High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.2220A>G	p.Gly740Gly	synonymous_variant	Exon 15 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.2220A>G	p.Gly740Gly	synonymous_variant	Exon 15 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.2220A>G	p.Gly740Gly	synonymous_variant	Exon 15 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.2220A>G	p.Gly740Gly	synonymous_variant	Exon 15 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.2310A>G	p.Gly770Gly	synonymous_variant	Exon 15 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.2220A>G	p.Gly740Gly	synonymous_variant	Exon 15 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.2220A>G	p.Gly740Gly	synonymous_variant	Exon 15 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.2385A>G	p.Gly795Gly	synonymous_variant	Exon 16 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.2220A>G	p.Gly740Gly	synonymous_variant	Exon 15 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.2220A>G	p.Gly740Gly	synonymous_variant	Exon 15 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.2220A>G	p.Gly740Gly	synonymous_variant	Exon 15 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.2220A>G	p.Gly740Gly	synonymous_variant	Exon 15 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.2310A>G	p.Gly770Gly	synonymous_variant	Exon 15 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.2310A>G	p.Gly770Gly	synonymous_variant	Exon 15 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.2310A>G	p.Gly770Gly	synonymous_variant	Exon 15 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.2310A>G	p.Gly770Gly	synonymous_variant	Exon 15 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.2220A>G	p.Gly740Gly	synonymous_variant	Exon 15 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.2295A>G	p.Gly765Gly	synonymous_variant	Exon 16 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.2220A>G	p.Gly740Gly	synonymous_variant	Exon 15 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.2220A>G	p.Gly740Gly	synonymous_variant	Exon 15 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.2220A>G	p.Gly740Gly	synonymous_variant	Exon 15 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.2220A>G	p.Gly740Gly	synonymous_variant	Exon 15 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.2220A>G	p.Gly740Gly	synonymous_variant	Exon 15 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.2295A>G	p.Gly765Gly	synonymous_variant	Exon 16 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.2220A>G	p.Gly740Gly	synonymous_variant	Exon 15 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.2220A>G	p.Gly740Gly	synonymous_variant	Exon 15 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.2220A>G	p.Gly740Gly	synonymous_variant	Exon 15 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.2220A>G	p.Gly740Gly	synonymous_variant	Exon 15 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.2220A>G	p.Gly740Gly	synonymous_variant	Exon 15 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.2220A>G	p.Gly740Gly	synonymous_variant	Exon 15 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.2220A>G	p.Gly740Gly	synonymous_variant	Exon 15 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.2220A>G	p.Gly740Gly	synonymous_variant	Exon 15 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.2211A>G	p.Gly737Gly	synonymous_variant	Exon 15 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.2220A>G	p.Gly740Gly	synonymous_variant	Exon 15 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.*827A>G		non_coding_transcript_exon_variant	Exon 13 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6 link	n.*827A>G		3_prime_UTR_variant	Exon 13 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152142

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

173054

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000919

AC:

AN:

1413860

Hom.:

Cov.:

AF XY:

0.0000100

AC XY:

AN XY:

698720

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32354

American (AMR)

AF:

0.00

AC:

AN:

37448

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25380

East Asian (EAS)

AF:

0.00

AC:

AN:

37448

South Asian (SAS)

AF:

0.00

AC:

AN:

80226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50482

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5386

European-Non Finnish (NFE)

AF:

0.0000120

AC:

AN:

1086532

Other (OTH)

AF:

0.00

AC:

AN:

58604

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

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:

152142

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41406

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2092

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:

0.0000329

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:1

Nov 21, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2220A>G variant (also known as p.G740G), located in coding exon 15 of the CACNA1C gene, results from an A to G substitution at nucleotide position 2220. This nucleotide substitution does not change the glycine at codon 740. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

CACNA1C-related disorder

Benign:1

May 06, 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). -

Long QT syndrome

Benign:1

Nov 30, 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

-0.58

CADD

Benign

8.5

(source)

DANN

Benign

0.78

PhyloP100

2.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.30

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.30

Position offset: 4

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