19-13207858-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBA1

The NM_001127222.2(CACNA1A):c.6973_6975dupCAG(p.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 0.034 ( 152 hom., cov: 0)

Exomes 𝑓: 0.039 ( 283 hom. )

Consequence

CACNA1A
NM_001127222.2 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
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, Labcorp Genetics (formerly Invitae), Ambry Genetics
migraine, familial hemiplegic, 1
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
spinocerebellar ataxia type 6
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, 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

new If you want to explore the variant's impact on the transcript NM_001127222.2, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001127222.2

BP6

Variant 19-13207858-C-CCTG is Benign according to our data. Variant chr19-13207858-C-CCTG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.133 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	UniProt
CACNA1A	NM_001127222.2	MANE Select	c.6973_6975dupCAG	p.Gln2325dup	conservative_inframe_insertion	Exon 47 of 47	NP_001120694.1	O00555-8
CACNA1A	NM_001127221.2	MANE Plus Clinical	c.185_187dupCAG		3_prime_UTR	Exon 47 of 47	NP_001120693.1	O00555-3
CACNA1A	NM_023035.3		c.6991_6993dupCAG	p.Gln2331dup	conservative_inframe_insertion	Exon 48 of 48	NP_075461.2	A0A087WW63

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1A	ENST00000360228.11	TSL:1 MANE Select	c.6973_6975dupCAG	p.Gln2325dup	conservative_inframe_insertion	Exon 47 of 47	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1	TSL:5	c.6991_6993dupCAG	p.Gln2331dup	conservative_inframe_insertion	Exon 48 of 48	ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7	TSL:5	c.6979_6981dupCAG	p.Gln2327dup	conservative_inframe_insertion	Exon 47 of 47	ENSP00000460092.3	A0A1C7CYY9

Frequencies

GnomAD3 genomes

AF:

0.0341

AC:

5032

AN:

147772

Hom.:

153

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0122

Gnomad AMI

AF:

0.0190

Gnomad AMR

AF:

0.0678

Gnomad ASJ

AF:

0.0215

Gnomad EAS

AF:

0.142

Gnomad SAS

AF:

0.0168

Gnomad FIN

AF:

0.0179

Gnomad MID

AF:

0.0300

Gnomad NFE

AF:

0.0363

Gnomad OTH

AF:

0.0332

GnomAD2 exomes

AF:

0.0572

AC:

2976

AN:

52038

AF XY:

0.0538

show subpopulations

Gnomad AFR exome

AF:

0.00812

Gnomad AMR exome

AF:

0.0971

Gnomad ASJ exome

AF:

0.0213

Gnomad EAS exome

AF:

0.193

Gnomad FIN exome

AF:

0.0295

Gnomad NFE exome

AF:

0.0482

Gnomad OTH exome

AF:

0.0539

GnomAD4 exome

AF:

0.0393

AC:

50492

AN:

1283302

Hom.:

283

Cov.:

AF XY:

0.0390

AC XY:

24609

AN XY:

631626

show subpopulations

African (AFR)

AF:

0.0128

AC:

318

AN:

24920

American (AMR)

AF:

0.0725

AC:

1747

AN:

24082

Ashkenazi Jewish (ASJ)

AF:

0.0185

AC:

402

AN:

21716

East Asian (EAS)

AF:

0.115

AC:

3411

AN:

29552

South Asian (SAS)

AF:

0.0211

AC:

1381

AN:

65546

European-Finnish (FIN)

AF:

0.0245

AC:

820

AN:

33408

Middle Eastern (MID)

AF:

0.0371

AC:

139

AN:

3750

European-Non Finnish (NFE)

AF:

0.0392

AC:

40227

AN:

1027206

Other (OTH)

AF:

0.0385

AC:

2047

AN:

53122

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

2535

5069

7604

10138

12673

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1600

3200

4800

6400

8000

<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:

0.0340

AC:

5023

AN:

147874

Hom.:

152

Cov.:

AF XY:

0.0350

AC XY:

2519

AN XY:

71986

show subpopulations

African (AFR)

AF:

0.0122

AC:

490

AN:

40202

American (AMR)

AF:

0.0675

AC:

1010

AN:

14962

Ashkenazi Jewish (ASJ)

AF:

0.0215

AC:

AN:

3436

East Asian (EAS)

AF:

0.141

AC:

681

AN:

4814

South Asian (SAS)

AF:

0.0168

AC:

AN:

4702

European-Finnish (FIN)

AF:

0.0179

AC:

178

AN:

9950

Middle Eastern (MID)

AF:

0.0290

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.0363

AC:

2419

AN:

66594

Other (OTH)

AF:

0.0328

AC:

AN:

2042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

219

437

656

874

1093

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0134

Hom.:

195

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

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

not specified (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

PhyloP100

0.0

Mutation Taster

=81/19

polymorphism (auto)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

Computational scores

Splicing

Publications

Other links and lift over