12-2504853-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.1125C>T(p.Ala375Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,579,566 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 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.90

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 -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.27).

BP6

Variant 12-2504853-C-T is Benign according to our data. Variant chr12-2504853-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 456944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.9 with no splicing effect.

BS2

High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.1125C>T	p.Ala375Ala	synonymous_variant	Exon 8 of 47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.1217+314C>T		intron_variant	Intron 8 of 46	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399655.6 link	c.1125C>T	p.Ala375Ala	synonymous_variant	Exon 8 of 47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.1215C>T	p.Ala405Ala	synonymous_variant	Exon 8 of 50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000347598.9 link	c.1125C>T	p.Ala375Ala	synonymous_variant	Exon 8 of 49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.1125C>T	p.Ala375Ala	synonymous_variant	Exon 8 of 47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.1125C>T	p.Ala375Ala	synonymous_variant	Exon 8 of 48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399638.5 link	c.1125C>T	p.Ala375Ala	synonymous_variant	Exon 8 of 48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.1125C>T	p.Ala375Ala	synonymous_variant	Exon 8 of 48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.1125C>T	p.Ala375Ala	synonymous_variant	Exon 8 of 48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.1125C>T	p.Ala375Ala	synonymous_variant	Exon 8 of 47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.1125C>T	p.Ala375Ala	synonymous_variant	Exon 8 of 47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.1125C>T	p.Ala375Ala	synonymous_variant	Exon 8 of 47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.1125C>T	p.Ala375Ala	synonymous_variant	Exon 8 of 47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.1125C>T	p.Ala375Ala	synonymous_variant	Exon 8 of 47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.1125C>T	p.Ala375Ala	synonymous_variant	Exon 8 of 46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.1125C>T	p.Ala375Ala	synonymous_variant	Exon 8 of 46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.1125C>T	p.Ala375Ala	synonymous_variant	Exon 8 of 46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.1125C>T	p.Ala375Ala	synonymous_variant	Exon 8 of 47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.1125C>T	p.Ala375Ala	synonymous_variant	Exon 8 of 47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399644.5 link	c.1125C>T	p.Ala375Ala	synonymous_variant	Exon 8 of 47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000683482.1 link	c.1116C>T	p.Ala372Ala	synonymous_variant	Exon 8 of 47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.1125C>T	p.Ala375Ala	synonymous_variant	Exon 8 of 46			ENSP00000507309.1	Q13936-19
CACNA1C	ENST00000399603.6 link	c.1217+314C>T		intron_variant	Intron 8 of 46	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000406454.8 link	c.1217+314C>T		intron_variant	Intron 8 of 47	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.1217+314C>T		intron_variant	Intron 8 of 46	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.1307+314C>T		intron_variant	Intron 8 of 47			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000399617.6 link	c.1217+314C>T		intron_variant	Intron 8 of 47	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.1307+314C>T		intron_variant	Intron 8 of 46			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.1307+314C>T		intron_variant	Intron 8 of 46			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.1307+314C>T		intron_variant	Intron 8 of 46			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.1307+314C>T		intron_variant	Intron 8 of 46			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399641.6 link	c.1217+314C>T		intron_variant	Intron 8 of 46	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000682835.1 link	c.1217+314C>T		intron_variant	Intron 8 of 46			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000480911.6 link	n.1113+11467C>T		intron_variant	Intron 7 of 26	5		ENSP00000437936.2	F5H638

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151764

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000201

AC:

AN:

248570

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000355

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000161

AC:

AN:

1427802

Hom.:

Cov.:

AF XY:

0.0000154

AC XY:

AN XY:

712636

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32828

American (AMR)

AF:

0.0000224

AC:

AN:

44670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25906

East Asian (EAS)

AF:

0.000126

AC:

AN:

39538

South Asian (SAS)

AF:

0.0000117

AC:

AN:

85436

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

1081136

Other (OTH)

AF:

0.00

AC:

AN:

59178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.432

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:

0.0000132

AC:

AN:

151764

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74076

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41340

American (AMR)

AF:

0.00

AC:

AN:

15220

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5106

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10538

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67978

Other (OTH)

AF:

0.00

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.0000151

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome

Benign:1

Oct 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Nov 21, 2019

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

-0.27

CADD

Benign

(source)

DANN

Benign

0.79

PhyloP100

1.9

PromoterAI

-0.011

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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