Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001127222.2(CACNA1A):c.6657T>C(p.His2219His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.615 in 1,452,354 control chromosomes in the GnomAD database, including 247,868 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H2219dup) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.67 ( 33746 hom., cov: 27)

Exomes 𝑓: 0.61 ( 214122 hom. )

Consequence

CACNA1A
NM_001127222.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17

Conservation

PhyloP100: 0.00

Publications

17 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:

ENSG00000300728 (HGNC:):

ENSG00000300728 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 19-13208879-A-G is Benign according to our data. Variant chr19-13208879-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.766 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127222.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNA1A	NM_001127222.2	MANE Select	c.6657T>C	p.His2219His	synonymous	Exon 46 of 47	NP_001120694.1
CACNA1A	NM_001127221.2	MANE Plus Clinical	c.6660T>C	p.His2220His	synonymous	Exon 46 of 47	NP_001120693.1
CACNA1A	NM_023035.3		c.6675T>C	p.His2225His	synonymous	Exon 47 of 48	NP_075461.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNA1A	ENST00000360228.11	TSL:1 MANE Select	c.6657T>C	p.His2219His	synonymous	Exon 46 of 47	ENSP00000353362.5
CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.6660T>C	p.His2220His	synonymous	Exon 46 of 47	ENSP00000489913.1
CACNA1A	ENST00000638029.1	TSL:5	c.6675T>C	p.His2225His	synonymous	Exon 47 of 48	ENSP00000489829.1

Frequencies

GnomAD3 genomes

AF:

0.671

AC:

99644

AN:

148490

Hom.:

33711

Cov.:

show subpopulations

Gnomad AFR

AF:

0.772

Gnomad AMI

AF:

0.603

Gnomad AMR

AF:

0.600

Gnomad ASJ

AF:

0.531

Gnomad EAS

AF:

0.787

Gnomad SAS

AF:

0.596

Gnomad FIN

AF:

0.739

Gnomad MID

AF:

0.435

Gnomad NFE

AF:

0.623

Gnomad OTH

AF:

0.609

GnomAD2 exomes

AF:

0.601

AC:

74602

AN:

124082

AF XY:

0.599

show subpopulations

Gnomad AFR exome

AF:

0.724

Gnomad AMR exome

AF:

0.562

Gnomad ASJ exome

AF:

0.520

Gnomad EAS exome

AF:

0.712

Gnomad FIN exome

AF:

0.676

Gnomad NFE exome

AF:

0.599

Gnomad OTH exome

AF:

0.574

GnomAD4 exome

AF:

0.608

AC:

792867

AN:

1303764

Hom.:

214122

Cov.:

AF XY:

0.605

AC XY:

390146

AN XY:

644622

show subpopulations

African (AFR)

AF:

0.727

AC:

21993

AN:

30266

American (AMR)

AF:

0.558

AC:

19181

AN:

34368

Ashkenazi Jewish (ASJ)

AF:

0.523

AC:

12325

AN:

23546

East Asian (EAS)

AF:

0.719

AC:

24592

AN:

34212

South Asian (SAS)

AF:

0.567

AC:

43519

AN:

76782

European-Finnish (FIN)

AF:

0.688

AC:

22348

AN:

32482

Middle Eastern (MID)

AF:

0.461

AC:

2209

AN:

4790

European-Non Finnish (NFE)

AF:

0.606

AC:

613940

AN:

1012986

Other (OTH)

AF:

0.603

AC:

32760

AN:

54332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

15664

31327

46991

62654

78318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17804

35608

53412

71216

89020

<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:

0.671

AC:

99736

AN:

148590

Hom.:

33746

Cov.:

AF XY:

0.675

AC XY:

48903

AN XY:

72412

show subpopulations

African (AFR)

AF:

0.773

AC:

31483

AN:

40742

American (AMR)

AF:

0.600

AC:

8993

AN:

14994

Ashkenazi Jewish (ASJ)

AF:

0.531

AC:

1812

AN:

3410

East Asian (EAS)

AF:

0.787

AC:

3857

AN:

4902

South Asian (SAS)

AF:

0.596

AC:

2694

AN:

4518

European-Finnish (FIN)

AF:

0.739

AC:

7380

AN:

9988

Middle Eastern (MID)

AF:

0.423

AC:

121

AN:

286

European-Non Finnish (NFE)

AF:

0.623

AC:

41600

AN:

66798

Other (OTH)

AF:

0.611

AC:

1270

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1587

3174

4762

6349

7936

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

790

1580

2370

3160

3950

<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:

0.498

Hom.:

1245

Bravo

AF:

0.660

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

not provided (2)

Developmental and epileptic encephalopathy, 42 (1)

Episodic ataxia type 2 (1)

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 (1)

Inborn genetic diseases (1)

Migraine, familial hemiplegic, 1 (1)

Spinocerebellar ataxia type 6 (1)

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4310716:Developmental and epileptic encephalopathy, 42 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

6.6

(source)

DANN

Benign

0.70

PhyloP100

0.0

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over