19-13207858-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG-CCTGCTGCTGCTGCTGCTGCTGCTG

Position:

• chr19-13207858-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG-CCTGCTGCTGCTGCTGCTGCTGCTG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.00

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]

ACMG classification

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/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6970_6975delCAGCAG	p.Gln2324_Gln2325del	conservative_inframe_deletion	47/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6970_6975delCAGCAG	p.Gln2324_Gln2325del	conservative_inframe_deletion	47/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6988_6993delCAGCAG	p.Gln2330_Gln2331del	conservative_inframe_deletion	48/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6976_6981delCAGCAG	p.Gln2326_Gln2327del	conservative_inframe_deletion	47/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6973_6978delCAGCAG	p.Gln2325_Gln2326del	conservative_inframe_deletion	47/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6973_6978delCAGCAG	p.Gln2325_Gln2326del	conservative_inframe_deletion	47/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6937_6942delCAGCAG	p.Gln2313_Gln2314del	conservative_inframe_deletion	46/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6832_6837delCAGCAG	p.Gln2278_Gln2279del	conservative_inframe_deletion	46/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389	c.*56_*61delCAGCAG		3_prime_UTR_variant	47/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432	c.*182_*187delCAGCAG		3_prime_UTR_variant	48/48	5		ENSP00000490617.1
CACNA1A	ENST00000635895	c.*182_*187delCAGCAG		3_prime_UTR_variant	47/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009	c.*182_*187delCAGCAG		3_prime_UTR_variant	47/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276	c.*182_*187delCAGCAG		3_prime_UTR_variant	46/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 57375 AN: 147566 Hom.: 12009 Cov.: 0 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

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

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.: 0 AF XY: 0.383 AC XY: 27560 AN XY: 71882

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

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 20, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2020	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Spinocerebellar ataxia type 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Episodic ataxia type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Migraine, familial hemiplegic, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Developmental and epileptic encephalopathy, 42 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs16054; hg19: chr19-13318672;