19-13207858-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG-CCTGCTGCTGCTGCTGCTGCTGCTG

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_001127222.2(CACNA1A):c.6970_6975delCAGCAG(p.Gln2324_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 0.308 in 1,259,014 control chromosomes in the GnomAD database, including 36,422 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 12013 hom., cov: 0)

Exomes 𝑓: 0.31 ( 36422 hom. )

Failed GnomAD Quality Control

Consequence

CACNA1A
NM_001127222.2 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.00

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 19-13207858-CCTGCTG-C is Benign according to our data. Variant chr19-13207858-CCTGCTG-C is described in ClinVar as [Likely_benign]. Clinvar id is 445458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-13207858-CCTGCTG-C is described in Lovd as [Benign]. Variant chr19-13207858-CCTGCTG-C is described in Lovd as [Likely_benign]. Variant chr19-13207858-CCTGCTG-C is described in Lovd as [Benign].

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.6970_6975delCAGCAG	p.Gln2324_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.6970_6975delCAGCAG	p.Gln2324_Gln2325del	conservative_inframe_deletion	Exon 47 of 47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 link	c.6988_6993delCAGCAG	p.Gln2330_Gln2331del	conservative_inframe_deletion	Exon 48 of 48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.6976_6981delCAGCAG	p.Gln2326_Gln2327del	conservative_inframe_deletion	Exon 47 of 47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.6973_6978delCAGCAG	p.Gln2325_Gln2326del	conservative_inframe_deletion	Exon 47 of 47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 link	c.6973_6978delCAGCAG	p.Gln2325_Gln2326del	conservative_inframe_deletion	Exon 47 of 47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 link	c.6937_6942delCAGCAG	p.Gln2313_Gln2314del	conservative_inframe_deletion	Exon 46 of 46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 link	c.6832_6837delCAGCAG	p.Gln2278_Gln2279del	conservative_inframe_deletion	Exon 46 of 46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636389 link	c.56_61delCAGCAG		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432 link	c.182_187delCAGCAG		3_prime_UTR_variant	Exon 48 of 48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000635895 link	c.182_187delCAGCAG		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009 link	c.182_187delCAGCAG		3_prime_UTR_variant	Exon 47 of 47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276 link	c.182_187delCAGCAG		3_prime_UTR_variant	Exon 46 of 46	5		ENSP00000489777.1	O00555-5
CACNA1A	ENST00000636549.1 link	c.182_187delCAGCAG		downstream_gene_variant		5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 link	c.182_187delCAGCAG		downstream_gene_variant		5		ENSP00000489715.1	A0A1B0GTI4

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

57375

AN:

147566

Hom.:

12009

Cov.:

FAILED QC

Gnomad AFR

AF:

0.534

Gnomad AMI

AF:

0.322

Gnomad AMR

AF:

0.426

Gnomad ASJ

AF:

0.431

Gnomad EAS

AF:

0.202

Gnomad SAS

AF:

0.403

Gnomad FIN

AF:

0.228

Gnomad MID

AF:

0.567

Gnomad NFE

AF:

0.327

Gnomad OTH

AF:

0.410

GnomAD3 exomes

AF:

0.245

AC:

12734

AN:

52038

Hom.:

2290

AF XY:

0.251

AC XY:

7506

AN XY:

29882

show subpopulations

Gnomad AFR exome

AF:

0.407

Gnomad AMR exome

AF:

0.279

Gnomad ASJ exome

AF:

0.283

Gnomad EAS exome

AF:

0.0873

Gnomad SAS exome

AF:

0.294

Gnomad FIN exome

AF:

0.174

Gnomad NFE exome

AF:

0.224

Gnomad OTH exome

AF:

0.258

GnomAD4 exome

AF:

0.308

AC:

387948

AN:

1259014

Hom.:

36422

AF XY:

0.309

AC XY:

191427

AN XY:

619668

show subpopulations

Gnomad4 AFR exome

AF:

0.483

Gnomad4 AMR exome

AF:

0.343

Gnomad4 ASJ exome

AF:

0.358

Gnomad4 EAS exome

AF:

0.209

Gnomad4 SAS exome

AF:

0.349

Gnomad4 FIN exome

AF:

0.225

Gnomad4 NFE exome

AF:

0.304

Gnomad4 OTH exome

AF:

0.323

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.389

AC:

57414

AN:

147668

Hom.:

12013

Cov.:

AF XY:

0.383

AC XY:

27560

AN XY:

71882

show subpopulations

Gnomad4 AFR

AF:

0.533

Gnomad4 AMR

AF:

0.427

Gnomad4 ASJ

AF:

0.431

Gnomad4 EAS

AF:

0.203

Gnomad4 SAS

AF:

0.402

Gnomad4 FIN

AF:

0.228

Gnomad4 NFE

AF:

0.327

Gnomad4 OTH

AF:

0.408

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jun 20, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 40% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 37. Only high quality variants are reported. -

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

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Episodic ataxia type 2

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Migraine, familial hemiplegic, 1

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Developmental and epileptic encephalopathy, 42

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over