12-2610549-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_ModerateBP6_Very_StrongBP7BS2

The NM_000719.7(CACNA1C):c.3567C>T(p.Cys1189Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000831 in 1,613,340 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.0470

Publications

3 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 -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 12-2610549-C-T is Benign according to our data. Variant chr12-2610549-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 308145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.047 with no splicing effect.

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.3567C>T	p.Cys1189Cys	synonymous_variant	Exon 28 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.3567C>T	p.Cys1189Cys	synonymous_variant	Exon 28 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.3567C>T	p.Cys1189Cys	synonymous_variant	Exon 28 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.3567C>T	p.Cys1189Cys	synonymous_variant	Exon 28 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.3717C>T	p.Cys1239Cys	synonymous_variant	Exon 29 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.3567C>T	p.Cys1189Cys	synonymous_variant	Exon 28 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.3567C>T	p.Cys1189Cys	synonymous_variant	Exon 28 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.3732C>T	p.Cys1244Cys	synonymous_variant	Exon 29 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.3627C>T	p.Cys1209Cys	synonymous_variant	Exon 29 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.3567C>T	p.Cys1189Cys	synonymous_variant	Exon 28 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.3567C>T	p.Cys1189Cys	synonymous_variant	Exon 28 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.3567C>T	p.Cys1189Cys	synonymous_variant	Exon 28 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.3657C>T	p.Cys1219Cys	synonymous_variant	Exon 28 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.3657C>T	p.Cys1219Cys	synonymous_variant	Exon 28 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.3657C>T	p.Cys1219Cys	synonymous_variant	Exon 28 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.3657C>T	p.Cys1219Cys	synonymous_variant	Exon 28 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.3567C>T	p.Cys1189Cys	synonymous_variant	Exon 28 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.3642C>T	p.Cys1214Cys	synonymous_variant	Exon 29 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.3627C>T	p.Cys1209Cys	synonymous_variant	Exon 29 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.3567C>T	p.Cys1189Cys	synonymous_variant	Exon 28 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.3567C>T	p.Cys1189Cys	synonymous_variant	Exon 28 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.3567C>T	p.Cys1189Cys	synonymous_variant	Exon 28 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.3567C>T	p.Cys1189Cys	synonymous_variant	Exon 28 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.3642C>T	p.Cys1214Cys	synonymous_variant	Exon 29 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.3567C>T	p.Cys1189Cys	synonymous_variant	Exon 28 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.3567C>T	p.Cys1189Cys	synonymous_variant	Exon 28 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.3567C>T	p.Cys1189Cys	synonymous_variant	Exon 28 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.3567C>T	p.Cys1189Cys	synonymous_variant	Exon 28 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.3567C>T	p.Cys1189Cys	synonymous_variant	Exon 28 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.3567C>T	p.Cys1189Cys	synonymous_variant	Exon 28 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.3567C>T	p.Cys1189Cys	synonymous_variant	Exon 28 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.3567C>T	p.Cys1189Cys	synonymous_variant	Exon 28 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.3558C>T	p.Cys1186Cys	synonymous_variant	Exon 28 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.3567C>T	p.Cys1189Cys	synonymous_variant	Exon 28 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.*2174C>T		non_coding_transcript_exon_variant	Exon 26 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6 link	n.*2174C>T		3_prime_UTR_variant	Exon 26 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152198

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:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000604

AC:

AN:

248420

AF XY:

0.0000520

show subpopulations

Gnomad AFR exome

AF:

0.0000646

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000500

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000267

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000862

AC:

126

AN:

1461024

Hom.:

Cov.:

AF XY:

0.0000894

AC XY:

AN XY:

726726

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33472

American (AMR)

AF:

0.0000224

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26074

East Asian (EAS)

AF:

0.000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86132

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000819

AC:

AN:

1111444

Other (OTH)

AF:

0.000365

AC:

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

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:

0.0000525

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41558

American (AMR)

AF:

0.0000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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:

0.000115

Hom.:

Bravo

AF:

0.0000491

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Dec 27, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

not specified

Benign:1

Jul 04, 2020

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1C-related disorder

Benign:1

Dec 16, 2023

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

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cardiovascular phenotype

Benign:1

May 15, 2017

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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.

Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long QT syndrome 8

Benign:1

Sep 28, 2021

Fulgent Genetics, Fulgent Genetics

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

-0.45

CADD

Benign

3.0

(source)

DANN

Benign

0.83

PhyloP100

-0.047

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