rs561224137

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_000719.7(CACNA1C):c.579C>T(p.Asn193Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000679 in 1,575,198 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 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000072 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.664

Publications

2 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:

ENSG00000285734 (HGNC:):

ENSG00000285734 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 12-2449077-C-T is Benign according to our data. Variant chr12-2449077-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 308130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.664 with no splicing effect.

BS2

High AC in GnomAdExome4 at 103 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.669C>T	p.Asn223Asn	synonymous_variant	Exon 4 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.669C>T	p.Asn223Asn	synonymous_variant	Exon 4 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.669C>T	p.Asn223Asn	synonymous_variant	Exon 4 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.669C>T	p.Asn223Asn	synonymous_variant	Exon 4 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.669C>T	p.Asn223Asn	synonymous_variant	Exon 4 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.669C>T	p.Asn223Asn	synonymous_variant	Exon 4 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.579C>T	p.Asn193Asn	synonymous_variant	Exon 4 of 46			ENSP00000507309.1
CACNA1C	ENST00000682152.1 link	c.528C>T	p.Asn176Asn	synonymous_variant	Exon 3 of 6			ENSP00000506759.1
CACNA1C	ENST00000480911.6 link	n.579C>T		non_coding_transcript_exon_variant	Exon 4 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152164

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:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000836

AC:

AN:

191416

AF XY:

0.000128

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000706

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000618

Gnomad OTH exome

AF:

0.000398

GnomAD4 exome

AF:

0.0000724

AC:

103

AN:

1422916

Hom.:

Cov.:

AF XY:

0.0000809

AC XY:

AN XY:

704186

show subpopulations

African (AFR)

AF:

0.0000610

AC:

AN:

32782

American (AMR)

AF:

0.0000264

AC:

AN:

37868

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25468

East Asian (EAS)

AF:

0.0000258

AC:

AN:

38802

South Asian (SAS)

AF:

0.000149

AC:

AN:

80572

European-Finnish (FIN)

AF:

0.0000194

AC:

AN:

51644

Middle Eastern (MID)

AF:

0.000351

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.0000678

AC:

AN:

1091016

Other (OTH)

AF:

0.000169

AC:

AN:

59070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

0.0000263

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41536

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

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:

0.0000943

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Oct 30, 2022

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 21, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Timothy syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Brugada syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Benign:1

Dec 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jul 10, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

5.1

(source)

DANN

Benign

0.65

PhyloP100

-0.66

Mutation Taster

=95/5

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

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