rs1800039

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001127222.2(CACNA1A):c.462C>T(p.Ala154Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00156 in 1,613,774 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0065 ( 17 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 17 hom. )

Consequence

CACNA1A
NM_001127222.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.542

Publications

1 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.32).

BP6

Variant 19-13452953-G-A is Benign according to our data. Variant chr19-13452953-G-A is described in ClinVar as Benign. ClinVar VariationId is 128554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.542 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00648 (987/152242) while in subpopulation AFR AF = 0.0214 (890/41526). AF 95% confidence interval is 0.0203. There are 17 homozygotes in GnomAd4. There are 472 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 987 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.462C>T	p.Ala154Ala	synonymous_variant	Exon 3 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2 link	c.462C>T	p.Ala154Ala	synonymous_variant	Exon 3 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1A	ENST00000360228.11 link	c.462C>T	p.Ala154Ala	synonymous_variant	Exon 3 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2 link	c.462C>T	p.Ala154Ala	synonymous_variant	Exon 3 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1 link	c.462C>T	p.Ala154Ala	synonymous_variant	Exon 3 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7 link	c.462C>T	p.Ala154Ala	synonymous_variant	Exon 3 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1 link	c.462C>T	p.Ala154Ala	synonymous_variant	Exon 3 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1 link	c.462C>T	p.Ala154Ala	synonymous_variant	Exon 3 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1 link	c.462C>T	p.Ala154Ala	synonymous_variant	Exon 3 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1 link	c.321C>T	p.Ala107Ala	synonymous_variant	Exon 2 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1 link	c.462C>T	p.Ala154Ala	synonymous_variant	Exon 3 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1 link	c.462C>T	p.Ala154Ala	synonymous_variant	Exon 3 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1 link	c.462C>T	p.Ala154Ala	synonymous_variant	Exon 3 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1 link	c.462C>T	p.Ala154Ala	synonymous_variant	Exon 3 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1 link	c.462C>T	p.Ala154Ala	synonymous_variant	Exon 3 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1 link	c.462C>T	p.Ala154Ala	synonymous_variant	Exon 3 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2 link	n.462C>T		non_coding_transcript_exon_variant	Exon 3 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.462C>T		non_coding_transcript_exon_variant	Exon 3 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

AF:

0.00647

AC:

985

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0214

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.0104

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:

0.00526

GnomAD2 exomes

AF:

0.00227

AC:

566

AN:

249284

AF XY:

0.00201

show subpopulations

Gnomad AFR exome

AF:

0.0243

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.0113

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000203

Gnomad OTH exome

AF:

0.00182

GnomAD4 exome

AF:

0.00105

AC:

1531

AN:

1461532

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

733

AN XY:

727062

show subpopulations

African (AFR)

AF:

0.0228

AC:

764

AN:

33476

American (AMR)

AF:

0.00123

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0109

AC:

285

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000223

AC:

248

AN:

1111706

Other (OTH)

AF:

0.00272

AC:

164

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

152

228

304

380

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00648

AC:

987

AN:

152242

Hom.:

Cov.:

AF XY:

0.00634

AC XY:

472

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0214

AC:

890

AN:

41526

American (AMR)

AF:

0.00255

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68018

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

139

186

232

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00431

Hom.:

Bravo

AF:

0.00776

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Oct 20, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 04, 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

May 18, 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

BayesDel_noAF

Benign

-0.32

CADD

Benign

8.9

(source)

DANN

Benign

0.72

PhyloP100

-0.54

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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