19-13207858-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001127222.2(CACNA1A):c.6970_6975dupCAGCAG(p.Gln2324_Gln2325dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 3 hom., cov: 0)

Exomes 𝑓: 0.0024 ( 23 hom. )

Consequence

CACNA1A
NM_001127222.2 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.00

Publications

10 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 -16 ACMG points.

BP6

Variant 19-13207858-C-CCTGCTG is Benign according to our data. Variant chr19-13207858-C-CCTGCTG is described in ClinVar as [Likely_benign]. Clinvar id is 1285153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00273 (404/147904) while in subpopulation EAS AF = 0.0139 (67/4816). AF 95% confidence interval is 0.0112. There are 3 homozygotes in GnomAd4. There are 225 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 404 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.6970_6975dupCAGCAG	p.Gln2324_Gln2325dup	conservative_inframe_insertion	Exon 47 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.6970_6975dupCAGCAG	p.Gln2324_Gln2325dup	conservative_inframe_insertion	Exon 47 of 47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 link	c.6988_6993dupCAGCAG	p.Gln2330_Gln2331dup	conservative_inframe_insertion	Exon 48 of 48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.6976_6981dupCAGCAG	p.Gln2326_Gln2327dup	conservative_inframe_insertion	Exon 47 of 47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.6973_6978dupCAGCAG	p.Gln2325_Gln2326dup	conservative_inframe_insertion	Exon 47 of 47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 link	c.6973_6978dupCAGCAG	p.Gln2325_Gln2326dup	conservative_inframe_insertion	Exon 47 of 47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 link	c.6937_6942dupCAGCAG	p.Gln2313_Gln2314dup	conservative_inframe_insertion	Exon 46 of 46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 link	c.6832_6837dupCAGCAG	p.Gln2278_Gln2279dup	conservative_inframe_insertion	Exon 46 of 46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636768.2 link	n.1231_1236dupCAGCAG		non_coding_transcript_exon_variant	Exon 45 of 45	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000713789.1 link	n.2149_2154dupCAGCAG		non_coding_transcript_exon_variant	Exon 47 of 47			ENSP00000519091.1
CACNA1A	ENST00000636389.1 link	c.56_61dupCAGCAG		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 link	c.182_187dupCAGCAG		3_prime_UTR_variant	Exon 48 of 48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000635895.1 link	c.182_187dupCAGCAG		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 link	c.182_187dupCAGCAG		3_prime_UTR_variant	Exon 47 of 47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 link	c.182_187dupCAGCAG		3_prime_UTR_variant	Exon 46 of 46	5		ENSP00000489777.1	O00555-5
CACNA1A	ENST00000636768.2 link	n.1231_1236dupCAGCAG		3_prime_UTR_variant	Exon 45 of 45	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000713789.1 link	n.2149_2154dupCAGCAG		3_prime_UTR_variant	Exon 47 of 47			ENSP00000519091.1
CACNA1A	ENST00000636549.1 link	c.182_187dupCAGCAG		downstream_gene_variant		5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 link	c.182_187dupCAGCAG		downstream_gene_variant		5		ENSP00000489715.1	A0A1B0GTI4

Frequencies

GnomAD3 genomes

AF:

0.00273

AC:

404

AN:

147802

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00249

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00368

Gnomad ASJ

AF:

0.000873

Gnomad EAS

AF:

0.0141

Gnomad SAS

AF:

0.00679

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.0267

Gnomad NFE

AF:

0.00176

Gnomad OTH

AF:

0.00297

GnomAD2 exomes

AF:

0.00527

AC:

274

AN:

52038

AF XY:

0.00509

show subpopulations

Gnomad AFR exome

AF:

0.00162

Gnomad AMR exome

AF:

0.00605

Gnomad ASJ exome

AF:

0.00147

Gnomad EAS exome

AF:

0.0195

Gnomad FIN exome

AF:

0.00181

Gnomad NFE exome

AF:

0.00223

Gnomad OTH exome

AF:

0.00526

GnomAD4 exome

AF:

0.00244

AC:

3128

AN:

1283858

Hom.:

Cov.:

AF XY:

0.00256

AC XY:

1615

AN XY:

631904

show subpopulations

African (AFR)

AF:

0.00289

AC:

AN:

24930

American (AMR)

AF:

0.00473

AC:

114

AN:

24096

Ashkenazi Jewish (ASJ)

AF:

0.00138

AC:

AN:

21718

East Asian (EAS)

AF:

0.0102

AC:

303

AN:

29576

South Asian (SAS)

AF:

0.00678

AC:

445

AN:

65600

European-Finnish (FIN)

AF:

0.00215

AC:

AN:

33418

Middle Eastern (MID)

AF:

0.00533

AC:

AN:

3752

European-Non Finnish (NFE)

AF:

0.00184

AC:

1893

AN:

1027626

Other (OTH)

AF:

0.00337

AC:

179

AN:

53142

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

132

263

395

526

658

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

164

246

328

410

<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:

0.00273

AC:

404

AN:

147904

Hom.:

Cov.:

AF XY:

0.00312

AC XY:

225

AN XY:

72002

show subpopulations

African (AFR)

AF:

0.00251

AC:

101

AN:

40206

American (AMR)

AF:

0.00367

AC:

AN:

14968

Ashkenazi Jewish (ASJ)

AF:

0.000873

AC:

AN:

3436

East Asian (EAS)

AF:

0.0139

AC:

AN:

4816

South Asian (SAS)

AF:

0.00680

AC:

AN:

4704

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

9952

Middle Eastern (MID)

AF:

0.0254

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.00177

AC:

118

AN:

66606

Other (OTH)

AF:

0.00294

AC:

AN:

2044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

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:

0.00

Hom.:

195

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1A: BS1, BS2 -

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

- -

not specified

Benign:1

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Benign:1

Nov 18, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.0

Mutation Taster

=81/19

polymorphism

(source)

Splicing

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