19-13207858-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG-CCTG

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.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:5

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: 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-CCTGCTGCTGCTGCTGCTGCTGCTGCTG-C is Benign according to our data. Variant chr19-13207858-CCTGCTGCTGCTGCTGCTGCTGCTGCTG-C is described in ClinVar as [Likely_benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.6949_6975delCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln2317_Gln2325del	conservative_inframe_deletion	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.6949_6975delCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln2317_Gln2325del	conservative_inframe_deletion	Exon 47 of 47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 link	c.6967_6993delCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln2323_Gln2331del	conservative_inframe_deletion	Exon 48 of 48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.6955_6981delCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln2319_Gln2327del	conservative_inframe_deletion	Exon 47 of 47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.6952_6978delCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln2318_Gln2326del	conservative_inframe_deletion	Exon 47 of 47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 link	c.6952_6978delCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln2318_Gln2326del	conservative_inframe_deletion	Exon 47 of 47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 link	c.6916_6942delCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln2306_Gln2314del	conservative_inframe_deletion	Exon 46 of 46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 link	c.6811_6837delCAGCAGCAGCAGCAGCAGCAGCAGCAG	p.Gln2271_Gln2279del	conservative_inframe_deletion	Exon 46 of 46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636768.2 link	n.1210_1236delCAGCAGCAGCAGCAGCAGCAGCAGCAG		non_coding_transcript_exon_variant	Exon 45 of 45	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000713789.1 link	n.2128_2154delCAGCAGCAGCAGCAGCAGCAGCAGCAG		non_coding_transcript_exon_variant	Exon 47 of 47			ENSP00000519091.1
CACNA1A	ENST00000636389.1 link	c.35_61delCAGCAGCAGCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 link	c.161_187delCAGCAGCAGCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 48 of 48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000635895.1 link	c.161_187delCAGCAGCAGCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 link	c.161_187delCAGCAGCAGCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 47 of 47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 link	c.161_187delCAGCAGCAGCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 46 of 46	5		ENSP00000489777.1	O00555-5
CACNA1A	ENST00000636768.2 link	n.1210_1236delCAGCAGCAGCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 45 of 45	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000713789.1 link	n.2128_2154delCAGCAGCAGCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 47 of 47			ENSP00000519091.1
CACNA1A	ENST00000636549.1 link	c.161_187delCAGCAGCAGCAGCAGCAGCAGCAGCAG		downstream_gene_variant		5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 link	c.161_187delCAGCAGCAGCAGCAGCAGCAGCAGCAG		downstream_gene_variant		5		ENSP00000489715.1	A0A1B0GTI4

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

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

Alfa

AF:

0.00688

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:2

Jun 02, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1A: BS1, BS2 -

not specified

Benign:1

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CACNA1A-related disorder

Benign:1

Sep 10, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Developmental and epileptic encephalopathy, 42

Benign:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

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

0.79

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over