19-13207858-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG

Position:

• chr19-13207858-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001127222.2(CACNA1A):​c.6970_6975dupCAGCAG​(p.Gln2324_Gln2325dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., cov: 0)
  • Exomes 𝑓: 0.0024 (23 hom.)
• Consequence: CACNA1A NM_001127222.2 conservative_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• 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-C-CCTGCTG is Benign according to our data. Variant chr19-13207858-C-CCTGCTG is described in ClinVar as [Likely_benign]. Clinvar id is 1285153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00273 (404/147904) while in subpopulation EAS AF= 0.0139 (67/4816). AF 95% confidence interval is 0.0112. There are 3 homozygotes in gnomad4. There are 225 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 404 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6970_6975dupCAGCAG	p.Gln2324_Gln2325dup	conservative_inframe_insertion	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_6975dupCAGCAG	p.Gln2324_Gln2325dup	conservative_inframe_insertion	47/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6988_6993dupCAGCAG	p.Gln2330_Gln2331dup	conservative_inframe_insertion	48/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6976_6981dupCAGCAG	p.Gln2326_Gln2327dup	conservative_inframe_insertion	47/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6973_6978dupCAGCAG	p.Gln2325_Gln2326dup	conservative_inframe_insertion	47/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6973_6978dupCAGCAG	p.Gln2325_Gln2326dup	conservative_inframe_insertion	47/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6937_6942dupCAGCAG	p.Gln2313_Gln2314dup	conservative_inframe_insertion	46/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6832_6837dupCAGCAG	p.Gln2278_Gln2279dup	conservative_inframe_insertion	46/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389	c.*56_*61dupCAGCAG		3_prime_UTR_variant	47/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432	c.*182_*187dupCAGCAG		3_prime_UTR_variant	48/48	5		ENSP00000490617.1
CACNA1A	ENST00000635895	c.*182_*187dupCAGCAG		3_prime_UTR_variant	47/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009	c.*182_*187dupCAGCAG		3_prime_UTR_variant	47/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276	c.*182_*187dupCAGCAG		3_prime_UTR_variant	46/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 404 AN: 147802 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00368

Gnomad ASJ AF: 0.000873

Gnomad EAS AF: 0.0141

Gnomad SAS AF: 0.00679

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0267

Gnomad NFE AF: 0.00176

Gnomad OTH AF: 0.00297

GnomAD3 exomes AF: 0.00527 AC: 274 AN: 52038 Hom.: 14 AF XY: 0.00509 AC XY: 152 AN XY: 29882

Gnomad AFR exome AF: 0.00162

Gnomad AMR exome AF: 0.00605

Gnomad ASJ exome AF: 0.00147

Gnomad EAS exome AF: 0.0195

Gnomad SAS exome AF: 0.0101

Gnomad FIN exome AF: 0.00181

Gnomad NFE exome AF: 0.00223

Gnomad OTH exome AF: 0.00526

GnomAD4 exome AF: 0.00244 AC: 3128 AN: 1283858 Hom.: 23 Cov.: 0 AF XY: 0.00256 AC XY: 1615 AN XY: 631904

Gnomad4 AFR exome AF: 0.00289

Gnomad4 AMR exome AF: 0.00473

Gnomad4 ASJ exome AF: 0.00138

Gnomad4 EAS exome AF: 0.0102

Gnomad4 SAS exome AF: 0.00678

Gnomad4 FIN exome AF: 0.00215

Gnomad4 NFE exome AF: 0.00184

Gnomad4 OTH exome AF: 0.00337

GnomAD4 genome AF: 0.00273 AC: 404 AN: 147904 Hom.: 3 Cov.: 0 AF XY: 0.00312 AC XY: 225 AN XY: 72002

Gnomad4 AFR AF: 0.00251

Gnomad4 AMR AF: 0.00367

Gnomad4 ASJ AF: 0.000873

Gnomad4 EAS AF: 0.0139

Gnomad4 SAS AF: 0.00680

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00177

Gnomad4 OTH AF: 0.00294

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CACNA1A: BS1, BS2 -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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- -

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4310716:Developmental and epileptic encephalopathy, 42 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 18, 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;