rs145549773

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 4P and 7B. PM1PM5BP4_ModerateBP6BS2

The NM_000719.7(CACNA1C):c.2566G>A(p.Gly856Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000694 in 1,613,708 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G856D) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000079 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.89

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: Likely_benign. The variant received -3 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000719.7

PM5

Other missense variant is known to change same aminoacid residue: Variant chr12-2593249-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3894932.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.22946781).

BP6

Variant 12-2593248-G-A is Benign according to our data. Variant chr12-2593248-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190652.

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.2566G>A	p.Gly856Ser	missense_variant	Exon 19 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.2566G>A	p.Gly856Ser	missense_variant	Exon 19 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.2566G>A	p.Gly856Ser	missense_variant	Exon 19 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.2566G>A	p.Gly856Ser	missense_variant	Exon 19 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.2656G>A	p.Gly886Ser	missense_variant	Exon 19 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.2566G>A	p.Gly856Ser	missense_variant	Exon 19 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.2566G>A	p.Gly856Ser	missense_variant	Exon 19 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.2731G>A	p.Gly911Ser	missense_variant	Exon 20 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.2566G>A	p.Gly856Ser	missense_variant	Exon 19 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.2566G>A	p.Gly856Ser	missense_variant	Exon 19 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.2566G>A	p.Gly856Ser	missense_variant	Exon 19 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.2566G>A	p.Gly856Ser	missense_variant	Exon 19 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.2656G>A	p.Gly886Ser	missense_variant	Exon 19 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.2656G>A	p.Gly886Ser	missense_variant	Exon 19 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.2656G>A	p.Gly886Ser	missense_variant	Exon 19 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.2656G>A	p.Gly886Ser	missense_variant	Exon 19 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.2566G>A	p.Gly856Ser	missense_variant	Exon 19 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.2641G>A	p.Gly881Ser	missense_variant	Exon 20 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.2566G>A	p.Gly856Ser	missense_variant	Exon 19 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.2566G>A	p.Gly856Ser	missense_variant	Exon 19 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.2566G>A	p.Gly856Ser	missense_variant	Exon 19 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.2566G>A	p.Gly856Ser	missense_variant	Exon 19 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.2566G>A	p.Gly856Ser	missense_variant	Exon 19 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.2641G>A	p.Gly881Ser	missense_variant	Exon 20 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.2566G>A	p.Gly856Ser	missense_variant	Exon 19 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.2566G>A	p.Gly856Ser	missense_variant	Exon 19 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.2566G>A	p.Gly856Ser	missense_variant	Exon 19 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.2566G>A	p.Gly856Ser	missense_variant	Exon 19 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.2566G>A	p.Gly856Ser	missense_variant	Exon 19 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.2566G>A	p.Gly856Ser	missense_variant	Exon 19 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.2566G>A	p.Gly856Ser	missense_variant	Exon 19 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.2566G>A	p.Gly856Ser	missense_variant	Exon 19 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.2557G>A	p.Gly853Ser	missense_variant	Exon 19 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.2566G>A	p.Gly856Ser	missense_variant	Exon 19 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.*1173G>A		non_coding_transcript_exon_variant	Exon 17 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6 link	n.*1173G>A		3_prime_UTR_variant	Exon 17 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000402

AC:

AN:

248558

AF XY:

0.0000519

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000581

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000557

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000621

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000684

AC:

100

AN:

1461432

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

726946

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33478

American (AMR)

AF:

0.0000671

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86124

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000828

AC:

AN:

1111770

Other (OTH)

AF:

0.0000166

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.0000788

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41544

American (AMR)

AF:

0.0000654

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.000139

Hom.:

Bravo

AF:

0.0000680

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Sep 12, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect -

Long QT syndrome

Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jan 08, 2024

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

AlphaMissense

Pathogenic

0.60

CardioboostArm

Benign

0.0041

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.068

T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.23

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.71

MutationAssessor

Benign

1.2

.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.

PhyloP100

5.9

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.9

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

REVEL

Pathogenic

0.72

Sift

Benign

0.29

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.40

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

1.0, 0.57, 0.88, 0.73, 0.99

.;D;D;P;P;P;D;D;D;P;D;D;D;D;D;D;.;D;D;.;D;.;D

Vest4

0.47

MVP

0.89

MPC

1.2

ClinPred

0.39

GERP RS

5.0

gMVP

0.58

Mutation Taster

=88/12

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

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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