19-13300637-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001127222.2(CACNA1A):c.2192A>C(p.Glu731Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0112 in 1,613,542 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.010 ( 21 hom., cov: 32)

Exomes 𝑓: 0.011 ( 111 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 5.03

Publications

14 publications found

Variant links:

Genes affected

CACNA1A (HGNC:1388): (calcium voltage-gated channel subunit alpha1 A) Voltage-dependent calcium channels mediate the entry of calcium ions into excitable cells, and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas, the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1A subunit, which is predominantly expressed in neuronal tissue. Mutations in this gene are associated with 2 neurologic disorders, familial hemiplegic migraine and episodic ataxia 2. This gene also exhibits polymorphic variation due to (CAG)n-repeats. Multiple transcript variants encoding different isoforms have been found for this gene. In one set of transcript variants, the (CAG)n-repeats occur in the 3' UTR, and are not associated with any disease. But in another set of variants, an insertion extends the coding region to include the (CAG)n-repeats which encode a polyglutamine tract. Expansion of the (CAG)n-repeats from the normal 4-18 to 21-33 in the coding region is associated with spinocerebellar ataxia 6. [provided by RefSeq, Jul 2016]

CACNA1A Gene-Disease associations (from GenCC):

episodic ataxia type 2
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Illumina
developmental and epileptic encephalopathy, 42
Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
migraine, familial hemiplegic, 1
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
spinocerebellar ataxia type 6
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
benign paroxysmal torticollis of infancy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
familial or sporadic hemiplegic migraine
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Lennox-Gastaut syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CACNA1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009210616).

BP6

Variant 19-13300637-T-G is Benign according to our data. Variant chr19-13300637-T-G is described in ClinVar as [Benign]. Clinvar id is 128547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0101 (1541/152282) while in subpopulation NFE AF = 0.0154 (1050/68018). AF 95% confidence interval is 0.0147. There are 21 homozygotes in GnomAd4. There are 763 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1541 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.2192A>C	p.Glu731Ala	missense_variant	Exon 18 of 47	ENST00000360228.11	NP_001120694.1	O00555-8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1A	ENST00000360228.11 link	c.2192A>C	p.Glu731Ala	missense_variant	Exon 18 of 47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 link	c.2204A>C	p.Glu735Ala	missense_variant	Exon 18 of 48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.2198A>C	p.Glu733Ala	missense_variant	Exon 18 of 47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.2195A>C	p.Glu732Ala	missense_variant	Exon 18 of 47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 link	c.2195A>C	p.Glu732Ala	missense_variant	Exon 18 of 47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 link	c.2195A>C	p.Glu732Ala	missense_variant	Exon 18 of 46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 link	c.2054A>C	p.Glu685Ala	missense_variant	Exon 17 of 46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636389.1 link	c.2195A>C	p.Glu732Ala	missense_variant	Exon 18 of 47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 link	c.2204A>C	p.Glu735Ala	missense_variant	Exon 18 of 48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000636549.1 link	c.2195A>C	p.Glu732Ala	missense_variant	Exon 18 of 48	5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 link	c.2198A>C	p.Glu733Ala	missense_variant	Exon 18 of 47	5		ENSP00000489715.1	A0A1B0GTI4
CACNA1A	ENST00000635895.1 link	c.2195A>C	p.Glu732Ala	missense_variant	Exon 18 of 47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 link	c.2195A>C	p.Glu732Ala	missense_variant	Exon 18 of 47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 link	c.2195A>C	p.Glu732Ala	missense_variant	Exon 18 of 46	5		ENSP00000489777.1	O00555-5
CACNA1A	ENST00000636768.2 link	n.2195A>C		non_coding_transcript_exon_variant	Exon 18 of 45	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000713789.1 link	n.2192A>C		non_coding_transcript_exon_variant	Exon 18 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

AF:

0.0101

AC:

1542

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00220

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.00504

Gnomad ASJ

AF:

0.00518

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.0248

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0154

Gnomad OTH

AF:

0.00716

GnomAD2 exomes

AF:

0.0105

AC:

2609

AN:

249304

AF XY:

0.0104

show subpopulations

Gnomad AFR exome

AF:

0.00207

Gnomad AMR exome

AF:

0.00469

Gnomad ASJ exome

AF:

0.00606

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0237

Gnomad NFE exome

AF:

0.0141

Gnomad OTH exome

AF:

0.0132

GnomAD4 exome

AF:

0.0113

AC:

16489

AN:

1461260

Hom.:

111

Cov.:

AF XY:

0.0113

AC XY:

8215

AN XY:

726972

show subpopulations

African (AFR)

AF:

0.00200

AC:

AN:

33472

American (AMR)

AF:

0.00523

AC:

234

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00509

AC:

133

AN:

26134

East Asian (EAS)

AF:

0.000227

AC:

AN:

39696

South Asian (SAS)

AF:

0.00572

AC:

493

AN:

86246

European-Finnish (FIN)

AF:

0.0222

AC:

1188

AN:

53394

Middle Eastern (MID)

AF:

0.0113

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0124

AC:

13735

AN:

1111468

Other (OTH)

AF:

0.00936

AC:

565

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

813

1626

2439

3252

4065

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0101

AC:

1541

AN:

152282

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

763

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00219

AC:

AN:

41562

American (AMR)

AF:

0.00504

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00518

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.00435

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0248

AC:

263

AN:

10610

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0154

AC:

1050

AN:

68018

Other (OTH)

AF:

0.00709

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

171

257

342

428

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0122

Hom.:

Bravo

AF:

0.00815

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.0114

AC:

ESP6500AA

AF:

0.00199

AC:

ESP6500EA

AF:

0.0134

AC:

112

ExAC

AF:

0.0101

AC:

1223

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0130

EpiControl

AF:

0.0140

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

May 24, 2016

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. -

Jun 02, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:4

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1A: PP2, BS1, BS2 -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Feb 24, 2016

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

Benign

0.12

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Benign

0.94

DEOGEN2

Pathogenic

0.83

.;D;T;.;.;.;.;.;.;T;.;.;.;T;.

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;D;D;.;D;D;D;D;D;D

MetaRNN

Benign

0.0092

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

MetaSVM

Uncertain

0.51

MutationAssessor

Benign

1.5

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

PhyloP100

5.0

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-5.5

.;D;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Uncertain

0.47

Sift

Benign

0.035

.;D;.;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Benign

0.091

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

Vest4

0.33

MPC

2.3

ClinPred

0.037

GERP RS

4.9

Varity_R

0.34

gMVP

0.89

Mutation Taster

=84/16

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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19-13300637-T-G

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