Genetic Variant CACNA1A:p.Gln2317_Gln2325del (chr19-13207858-CCTGCTGCTGCTGCTGCTGCTGCTGCTG-C) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_001127222.2(CACNA1A):c.6949_6975delCAGCAGCAGCAGCAGCAGCAGCAGCAG(p.Gln2317_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 0.00712 in 1,431,364 control chromosomes in the GnomAD database, including 69 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0075 ( 11 hom., cov: 0)

Exomes 𝑓: 0.0071 ( 58 hom. )

Consequence

CACNA1A
NM_001127222.2 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

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

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-CCTGCTGCTGCTGCTGCTGCTGCTGCTG-C is Benign according to our data. Variant chr19-13207858-CCTGCTGCTGCTGCTGCTGCTGCTGCTG-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 982691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00748 (1106/147898) while in subpopulation AMR AF = 0.0203 (304/14966). AF 95% confidence interval is 0.0184. There are 11 homozygotes in GnomAd4. There are 572 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 1106 AD gene.

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.6949_6975delCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln2317_Gln2325del	conservative_inframe_deletion	Exon 47 of 47	NP_001120694.1	O00555-8
CACNA1A	NM_001127221.2	MANE Plus Clinical	c.161_187delCAGCAGCAGCAGCAGCAGCAGCAGCAG		3_prime_UTR	Exon 47 of 47	NP_001120693.1	O00555-3
CACNA1A	NM_023035.3		c.6967_6993delCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln2323_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.6949_6975delCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln2317_Gln2325del	conservative_inframe_deletion	Exon 47 of 47	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1	TSL:5	c.6967_6993delCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln2323_Gln2331del	conservative_inframe_deletion	Exon 48 of 48	ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7	TSL:5	c.6955_6981delCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln2319_Gln2327del	conservative_inframe_deletion	Exon 47 of 47	ENSP00000460092.3	A0A1C7CYY9

Frequencies

GnomAD3 genomes

AF:

0.00745

AC:

1101

AN:

147796

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00210

Gnomad AMI

AF:

0.0402

Gnomad AMR

AF:

0.0202

Gnomad ASJ

AF:

0.000291

Gnomad EAS

AF:

0.00973

Gnomad SAS

AF:

0.00955

Gnomad FIN

AF:

0.00623

Gnomad MID

AF:

0.00333

Gnomad NFE

AF:

0.00755

Gnomad OTH

AF:

0.00989

GnomAD4 exome

AF:

0.00708

AC:

9090

AN:

1283466

Hom.:

AF XY:

0.00706

AC XY:

4461

AN XY:

631668

show subpopulations

African (AFR)

AF:

0.00152

AC:

AN:

24926

American (AMR)

AF:

0.0108

AC:

260

AN:

24060

Ashkenazi Jewish (ASJ)

AF:

0.000368

AC:

AN:

21718

East Asian (EAS)

AF:

0.00764

AC:

226

AN:

29594

South Asian (SAS)

AF:

0.00545

AC:

357

AN:

65496

European-Finnish (FIN)

AF:

0.00674

AC:

225

AN:

33394

Middle Eastern (MID)

AF:

0.00453

AC:

AN:

3750

European-Non Finnish (NFE)

AF:

0.00740

AC:

7600

AN:

1027396

Other (OTH)

AF:

0.00676

AC:

359

AN:

53132

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

390

780

1171

1561

1951

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

330

660

990

1320

1650

<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:

0.00748

AC:

1106

AN:

147898

Hom.:

Cov.:

AF XY:

0.00794

AC XY:

572

AN XY:

71998

show subpopulations

African (AFR)

AF:

0.00206

AC:

AN:

40206

American (AMR)

AF:

0.0203

AC:

304

AN:

14966

Ashkenazi Jewish (ASJ)

AF:

0.000291

AC:

AN:

3436

East Asian (EAS)

AF:

0.00976

AC:

AN:

4816

South Asian (SAS)

AF:

0.00935

AC:

AN:

4704

European-Finnish (FIN)

AF:

0.00623

AC:

AN:

9952

Middle Eastern (MID)

AF:

0.00362

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.00755

AC:

503

AN:

66602

Other (OTH)

AF:

0.0122

AC:

AN:

2044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

136

181

226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00688

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)

CACNA1A-related disorder (1)

Developmental and epileptic encephalopathy, 42 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.79

Mutation Taster

=193/7

polymorphism

(source)

Splicing

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

Publications

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19-13207858-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG-CCTG

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