19-13207858-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG

Position:

chr19-13207858-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG

Variant summary

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

The NM_001127222.2(CACNA1A):c.6973_6975dupCAG(p.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 0.034 ( 152 hom., cov: 0)

Exomes 𝑓: 0.039 ( 283 hom. )

Consequence

CACNA1A
NM_001127222.2 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

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

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-C-CCTG is Benign according to our data. Variant chr19-13207858-C-CCTG is described in ClinVar as [Likely_benign]. Clinvar id is 235603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.6973_6975dupCAG	p.Gln2325dup	conservative_inframe_insertion	47/47	ENST00000360228.11	NP_001120694.1	O00555-8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1A	ENST00000360228.11 link	c.6973_6975dupCAG	p.Gln2325dup	conservative_inframe_insertion	47/47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 link	c.6991_6993dupCAG	p.Gln2331dup	conservative_inframe_insertion	48/48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.6979_6981dupCAG	p.Gln2327dup	conservative_inframe_insertion	47/47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.6976_6978dupCAG	p.Gln2326dup	conservative_inframe_insertion	47/47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 link	c.6976_6978dupCAG	p.Gln2326dup	conservative_inframe_insertion	47/47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 link	c.6940_6942dupCAG	p.Gln2314dup	conservative_inframe_insertion	46/46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 link	c.6835_6837dupCAG	p.Gln2279dup	conservative_inframe_insertion	46/46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636389 link	c.59_61dupCAG		3_prime_UTR_variant	47/47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432 link	c.185_187dupCAG		3_prime_UTR_variant	48/48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000635895 link	c.185_187dupCAG		3_prime_UTR_variant	47/47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009 link	c.185_187dupCAG		3_prime_UTR_variant	47/47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276 link	c.185_187dupCAG		3_prime_UTR_variant	46/46	5		ENSP00000489777.1	O00555-5

Frequencies

GnomAD3 genomes

AF:

0.0341

AC:

5032

AN:

147772

Hom.:

153

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0122

Gnomad AMI

AF:

0.0190

Gnomad AMR

AF:

0.0678

Gnomad ASJ

AF:

0.0215

Gnomad EAS

AF:

0.142

Gnomad SAS

AF:

0.0168

Gnomad FIN

AF:

0.0179

Gnomad MID

AF:

0.0300

Gnomad NFE

AF:

0.0363

Gnomad OTH

AF:

0.0332

GnomAD3 exomes

AF:

0.0572

AC:

2976

AN:

52038

Hom.:

AF XY:

0.0538

AC XY:

1609

AN XY:

29882

show subpopulations

Gnomad AFR exome

AF:

0.00812

Gnomad AMR exome

AF:

0.0971

Gnomad ASJ exome

AF:

0.0213

Gnomad EAS exome

AF:

0.193

Gnomad SAS exome

AF:

0.0285

Gnomad FIN exome

AF:

0.0295

Gnomad NFE exome

AF:

0.0482

Gnomad OTH exome

AF:

0.0539

GnomAD4 exome

AF:

0.0393

AC:

50492

AN:

1283302

Hom.:

283

Cov.:

AF XY:

0.0390

AC XY:

24609

AN XY:

631626

show subpopulations

Gnomad4 AFR exome

AF:

0.0128

Gnomad4 AMR exome

AF:

0.0725

Gnomad4 ASJ exome

AF:

0.0185

Gnomad4 EAS exome

AF:

0.115

Gnomad4 SAS exome

AF:

0.0211

Gnomad4 FIN exome

AF:

0.0245

Gnomad4 NFE exome

AF:

0.0392

Gnomad4 OTH exome

AF:

0.0385

GnomAD4 genome

AF:

0.0340

AC:

5023

AN:

147874

Hom.:

152

Cov.:

AF XY:

0.0350

AC XY:

2519

AN XY:

71986

show subpopulations

Gnomad4 AFR

AF:

0.0122

Gnomad4 AMR

AF:

0.0675

Gnomad4 ASJ

AF:

0.0215

Gnomad4 EAS

AF:

0.141

Gnomad4 SAS

AF:

0.0168

Gnomad4 FIN

AF:

0.0179

Gnomad4 NFE

AF:

0.0363

Gnomad4 OTH

AF:

0.0328

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 09, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

- -

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

- -

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

Apr 07, 2022

- -

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