12-2648495-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.3933C>T(p.Cys1311Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000874 in 1,613,900 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 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.507

Publications

1 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=-0.37).

BP6

Variant 12-2648495-C-T is Benign according to our data. Variant chr12-2648495-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.507 with no splicing effect.

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.3933C>T	p.Cys1311Cys	synonymous_variant	Exon 31 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.3933C>T	p.Cys1311Cys	synonymous_variant	Exon 31 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.3933C>T	p.Cys1311Cys	synonymous_variant	Exon 31 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.3933C>T	p.Cys1311Cys	synonymous_variant	Exon 31 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.4167C>T	p.Cys1389Cys	synonymous_variant	Exon 33 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.3933C>T	p.Cys1311Cys	synonymous_variant	Exon 31 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000683824.1 link	c.4098C>T	p.Cys1366Cys	synonymous_variant	Exon 32 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.4077C>T	p.Cys1359Cys	synonymous_variant	Exon 33 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.3933C>T	p.Cys1311Cys	synonymous_variant	Exon 31 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.3933C>T	p.Cys1311Cys	synonymous_variant	Exon 31 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.3933C>T	p.Cys1311Cys	synonymous_variant	Exon 31 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.4023C>T	p.Cys1341Cys	synonymous_variant	Exon 31 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.4023C>T	p.Cys1341Cys	synonymous_variant	Exon 31 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.4023C>T	p.Cys1341Cys	synonymous_variant	Exon 31 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.4023C>T	p.Cys1341Cys	synonymous_variant	Exon 31 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.4017C>T	p.Cys1339Cys	synonymous_variant	Exon 32 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.4008C>T	p.Cys1336Cys	synonymous_variant	Exon 32 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.3993C>T	p.Cys1331Cys	synonymous_variant	Exon 32 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.3933C>T	p.Cys1311Cys	synonymous_variant	Exon 31 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.3933C>T	p.Cys1311Cys	synonymous_variant	Exon 31 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.3933C>T	p.Cys1311Cys	synonymous_variant	Exon 31 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399597.5 link	c.3933C>T	p.Cys1311Cys	synonymous_variant	Exon 31 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.3933C>T	p.Cys1311Cys	synonymous_variant	Exon 31 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.3933C>T	p.Cys1311Cys	synonymous_variant	Exon 31 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.3933C>T	p.Cys1311Cys	synonymous_variant	Exon 31 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.3933C>T	p.Cys1311Cys	synonymous_variant	Exon 31 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.3924C>T	p.Cys1308Cys	synonymous_variant	Exon 31 of 47			ENSP00000507169.1
CACNA1C	ENST00000399634.6 link	c.3913-3145C>T		intron_variant	Intron 30 of 46	5		ENSP00000382542.2
CACNA1C	ENST00000399629.5 link	c.3997-3145C>T		intron_variant	Intron 31 of 46	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.3988-3145C>T		intron_variant	Intron 31 of 46			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.3913-3145C>T		intron_variant	Intron 30 of 45	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.3913-3145C>T		intron_variant	Intron 30 of 45	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.3907-3145C>T		intron_variant	Intron 30 of 45	1		ENSP00000382557.1
CACNA1C	ENST00000682686.1 link	c.3913-3145C>T		intron_variant	Intron 30 of 45			ENSP00000507309.1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000682

AC:

AN:

249278

AF XY:

0.0000665

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000896

AC:

131

AN:

1461598

Hom.:

Cov.:

AF XY:

0.0000853

AC XY:

AN XY:

727096

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000112

AC:

125

AN:

1111780

Other (OTH)

AF:

0.0000663

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

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:

0.0000657

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41570

American (AMR)

AF:

0.00

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.00

Hom.:

Bravo

AF:

0.0000529

EpiCase

AF:

0.000436

EpiControl

AF:

0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Jul 10, 2011

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. -

Long QT syndrome

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Dec 14, 2020

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

-0.37

CADD

Benign

(source)

DANN

Benign

0.73

PhyloP100

0.51

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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