chr19-13207858-CCTGCTGCTGCTGCTGCTG-C

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.6958_6975delCAGCAGCAGCAGCAGCAG(p.Gln2320_Gln2325del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0852 in 1,278,312 control chromosomes in the GnomAD database, including 4,615 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q2320Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.090 ( 758 hom., cov: 0)

Exomes 𝑓: 0.085 ( 4615 hom. )

Failed GnomAD Quality Control

Consequence

CACNA1A
NM_001127222.2 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.785

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, Orphanet
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
spinocerebellar ataxia type 6
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
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 -17 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001127222.2

BP6

Variant 19-13207858-CCTGCTGCTGCTGCTGCTG-C is Benign according to our data. Variant chr19-13207858-CCTGCTGCTGCTGCTGCTG-C is described in ClinVar as Benign. ClinVar VariationId is 1249720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.107 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.6958_6975delCAGCAGCAGCAGCAGCAG	p.Gln2320_Gln2325del	conservative_inframe_deletion	Exon 47 of 47	NP_001120694.1	O00555-8
CACNA1A	NM_001127221.2	MANE Plus Clinical	c.170_187delCAGCAGCAGCAGCAGCAG		3_prime_UTR	Exon 47 of 47	NP_001120693.1	O00555-3
CACNA1A	NM_023035.3		c.6976_6993delCAGCAGCAGCAGCAGCAG	p.Gln2326_Gln2331del	conservative_inframe_deletion	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.6958_6975delCAGCAGCAGCAGCAGCAG	p.Gln2320_Gln2325del	conservative_inframe_deletion	Exon 47 of 47	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1	TSL:5	c.6976_6993delCAGCAGCAGCAGCAGCAG	p.Gln2326_Gln2331del	conservative_inframe_deletion	Exon 48 of 48	ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7	TSL:5	c.6964_6981delCAGCAGCAGCAGCAGCAG	p.Gln2322_Gln2327del	conservative_inframe_deletion	Exon 47 of 47	ENSP00000460092.3	A0A1C7CYY9

Frequencies

GnomAD3 genomes

AF:

0.0896

AC:

13235

AN:

147746

Hom.:

756

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0579

Gnomad AMI

AF:

0.0268

Gnomad AMR

AF:

0.0597

Gnomad ASJ

AF:

0.0562

Gnomad EAS

AF:

0.0905

Gnomad SAS

AF:

0.162

Gnomad FIN

AF:

0.197

Gnomad MID

AF:

0.0667

Gnomad NFE

AF:

0.0967

Gnomad OTH

AF:

0.0936

GnomAD2 exomes

AF:

0.0194

AC:

1007

AN:

52038

AF XY:

0.0199

show subpopulations

Gnomad AFR exome

AF:

0.0146

Gnomad AMR exome

AF:

0.00605

Gnomad ASJ exome

AF:

0.00930

Gnomad EAS exome

AF:

0.00420

Gnomad FIN exome

AF:

0.0397

Gnomad NFE exome

AF:

0.0237

Gnomad OTH exome

AF:

0.0177

GnomAD4 exome

AF:

0.0852

AC:

108948

AN:

1278312

Hom.:

4615

AF XY:

0.0847

AC XY:

53227

AN XY:

628184

show subpopulations

African (AFR)

AF:

0.0532

AC:

1326

AN:

24910

American (AMR)

AF:

0.0274

AC:

659

AN:

24028

Ashkenazi Jewish (ASJ)

AF:

0.0471

AC:

1020

AN:

21650

East Asian (EAS)

AF:

0.0635

AC:

1877

AN:

29540

South Asian (SAS)

AF:

0.109

AC:

7009

AN:

64032

European-Finnish (FIN)

AF:

0.149

AC:

4942

AN:

33078

Middle Eastern (MID)

AF:

0.0865

AC:

323

AN:

3736

European-Non Finnish (NFE)

AF:

0.0853

AC:

87387

AN:

1024442

Other (OTH)

AF:

0.0833

AC:

4405

AN:

52896

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

4329

8658

12987

17316

21645

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3530

7060

10590

14120

17650

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0896

AC:

13254

AN:

147848

Hom.:

758

Cov.:

AF XY:

0.0951

AC XY:

6847

AN XY:

71964

show subpopulations

African (AFR)

AF:

0.0579

AC:

2329

AN:

40194

American (AMR)

AF:

0.0594

AC:

889

AN:

14960

Ashkenazi Jewish (ASJ)

AF:

0.0562

AC:

193

AN:

3436

East Asian (EAS)

AF:

0.0904

AC:

435

AN:

4812

South Asian (SAS)

AF:

0.162

AC:

762

AN:

4700

European-Finnish (FIN)

AF:

0.197

AC:

1957

AN:

9936

Middle Eastern (MID)

AF:

0.0688

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.0967

AC:

6441

AN:

66596

Other (OTH)

AF:

0.100

AC:

205

AN:

2042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

557

1113

1670

2226

2783

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

328

492

656

820

<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:

0.0669

Hom.:

195

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (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

0.79

Mutation Taster

=197/3

polymorphism (auto)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over