rs28413664

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001127222.2(CACNA1A):c.3028C>G(p.Pro1010Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00395 in 1,538,708 control chromosomes in the GnomAD database, including 199 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 119 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 80 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.717

Publications

2 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=0.0019551814).

BP6

Variant 19-13298605-G-C is Benign according to our data. Variant chr19-13298605-G-C is described in ClinVar as Benign. ClinVar VariationId is 128550.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.3028C>G	p.Pro1010Ala	missense_variant	Exon 19 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.3028C>G	p.Pro1010Ala	missense_variant	Exon 19 of 47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 link	c.3040C>G	p.Pro1014Ala	missense_variant	Exon 19 of 48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.3034C>G	p.Pro1012Ala	missense_variant	Exon 19 of 47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.3031C>G	p.Pro1011Ala	missense_variant	Exon 19 of 47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 link	c.3031C>G	p.Pro1011Ala	missense_variant	Exon 19 of 47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 link	c.3031C>G	p.Pro1011Ala	missense_variant	Exon 19 of 46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 link	c.2890C>G	p.Pro964Ala	missense_variant	Exon 18 of 46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636389.1 link	c.3031C>G	p.Pro1011Ala	missense_variant	Exon 19 of 47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 link	c.3040C>G	p.Pro1014Ala	missense_variant	Exon 19 of 48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000636549.1 link	c.3031C>G	p.Pro1011Ala	missense_variant	Exon 19 of 48	5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 link	c.3034C>G	p.Pro1012Ala	missense_variant	Exon 19 of 47	5		ENSP00000489715.1	A0A1B0GTI4
CACNA1A	ENST00000635895.1 link	c.3031C>G	p.Pro1011Ala	missense_variant	Exon 19 of 47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 link	c.3031C>G	p.Pro1011Ala	missense_variant	Exon 19 of 47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 link	c.3031C>G	p.Pro1011Ala	missense_variant	Exon 19 of 46	5		ENSP00000489777.1	O00555-5
CACNA1A	ENST00000636768.2 link	n.3031C>G		non_coding_transcript_exon_variant	Exon 19 of 45	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000713789.1 link	n.3028C>G		non_coding_transcript_exon_variant	Exon 19 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

AF:

0.0216

AC:

3276

AN:

152008

Hom.:

118

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0732

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0121

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.0225

GnomAD2 exomes

AF:

0.00383

AC:

539

AN:

140816

AF XY:

0.00302

show subpopulations

Gnomad AFR exome

AF:

0.0808

Gnomad AMR exome

AF:

0.00350

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000268

Gnomad OTH exome

AF:

0.00282

GnomAD4 exome

AF:

0.00201

AC:

2789

AN:

1386584

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

1178

AN XY:

683836

show subpopulations

African (AFR)

AF:

0.0735

AC:

2163

AN:

29430

American (AMR)

AF:

0.00436

AC:

152

AN:

34836

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24714

East Asian (EAS)

AF:

0.00

AC:

AN:

33632

South Asian (SAS)

AF:

0.0000508

AC:

AN:

78734

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49116

Middle Eastern (MID)

AF:

0.00283

AC:

AN:

5648

European-Non Finnish (NFE)

AF:

0.000166

AC:

178

AN:

1073152

Other (OTH)

AF:

0.00481

AC:

276

AN:

57322

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

141

282

422

563

704

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<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:

0.0216

AC:

3285

AN:

152124

Hom.:

119

Cov.:

AF XY:

0.0205

AC XY:

1528

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.0732

AC:

3041

AN:

41518

American (AMR)

AF:

0.0120

AC:

184

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

67982

Other (OTH)

AF:

0.0223

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

168

335

503

670

838

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.00605

Hom.:

Bravo

AF:

0.0250

ESP6500AA

AF:

0.0628

AC:

195

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00648

AC:

198

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Sep 05, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

- -

not specified

Benign:2

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. -

Feb 01, 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. -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 15, 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

0.049

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.32

CADD

Benign

9.8

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.028

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

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.82

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

MetaRNN

Benign

0.0020

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

MetaSVM

Benign

-0.43

MutationAssessor

Benign

0.97

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

PhyloP100

-0.72

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-1.6

.;N;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Benign

0.21

Sift

Benign

0.23

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

Sift4G

Benign

0.58

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

Vest4

0.17

MVP

0.71

MPC

1.1

ClinPred

0.0034

GERP RS

3.0

Varity_R

0.071

gMVP

0.28

Mutation Taster

=97/3

polymorphism (auto)

(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