19-13207858-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG-CCTGCTGCTGCTGCTGCTGCTG

Position:

chr19-13207858-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG-CCTGCTGCTGCTGCTGCTGCTG

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_001127222.2(CACNA1A):c.6967_6975delCAGCAGCAG(p.Gln2323_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 0.00275 in 1,370,548 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0033 ( 3 hom., cov: 0)

Exomes 𝑓: 0.0027 ( 4 hom. )

Consequence

CACNA1A
NM_001127222.2 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.785

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 -10 ACMG points.

BP6

Variant 19-13207858-CCTGCTGCTG-C is Benign according to our data. Variant chr19-13207858-CCTGCTGCTG-C is described in ClinVar as [Likely_benign]. Clinvar id is 2578818.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-13207858-CCTGCTGCTG-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00325 (481/147858) while in subpopulation AFR AF= 0.00963 (387/40188). AF 95% confidence interval is 0.00884. There are 3 homozygotes in gnomad4. There are 226 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

BS2

High AC in GnomAd4 at 481 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.6967_6975delCAGCAGCAG	p.Gln2323_Gln2325del	conservative_inframe_deletion	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.6967_6975delCAGCAGCAG	p.Gln2323_Gln2325del	conservative_inframe_deletion	47/47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 link	c.6985_6993delCAGCAGCAG	p.Gln2329_Gln2331del	conservative_inframe_deletion	48/48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.6973_6981delCAGCAGCAG	p.Gln2325_Gln2327del	conservative_inframe_deletion	47/47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.6970_6978delCAGCAGCAG	p.Gln2324_Gln2326del	conservative_inframe_deletion	47/47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 link	c.6970_6978delCAGCAGCAG	p.Gln2324_Gln2326del	conservative_inframe_deletion	47/47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 link	c.6934_6942delCAGCAGCAG	p.Gln2312_Gln2314del	conservative_inframe_deletion	46/46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 link	c.6829_6837delCAGCAGCAG	p.Gln2277_Gln2279del	conservative_inframe_deletion	46/46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636389 link	c.53_61delCAGCAGCAG		3_prime_UTR_variant	47/47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432 link	c.179_187delCAGCAGCAG		3_prime_UTR_variant	48/48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000635895 link	c.179_187delCAGCAGCAG		3_prime_UTR_variant	47/47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009 link	c.179_187delCAGCAGCAG		3_prime_UTR_variant	47/47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276 link	c.179_187delCAGCAGCAG		3_prime_UTR_variant	46/46	5		ENSP00000489777.1	O00555-5

Frequencies

GnomAD3 genomes

AF:

0.00324

AC:

478

AN:

147756

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00961

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00134

Gnomad ASJ

AF:

0.00378

Gnomad EAS

AF:

0.00207

Gnomad SAS

AF:

0.00149

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000586

Gnomad OTH

AF:

0.00198

GnomAD3 exomes

AF:

0.00563

AC:

293

AN:

52038

Hom.:

AF XY:

0.00609

AC XY:

182

AN XY:

29882

show subpopulations

Gnomad AFR exome

AF:

0.0146

Gnomad AMR exome

AF:

0.00657

Gnomad ASJ exome

AF:

0.0103

Gnomad EAS exome

AF:

0.00114

Gnomad SAS exome

AF:

0.00777

Gnomad FIN exome

AF:

0.00211

Gnomad NFE exome

AF:

0.00431

Gnomad OTH exome

AF:

0.00329

GnomAD4 exome

AF:

0.00269

AC:

3293

AN:

1222690

Hom.:

AF XY:

0.00289

AC XY:

1735

AN XY:

601300

show subpopulations

Gnomad4 AFR exome

AF:

0.0146

Gnomad4 AMR exome

AF:

0.00838

Gnomad4 ASJ exome

AF:

0.00729

Gnomad4 EAS exome

AF:

0.00184

Gnomad4 SAS exome

AF:

0.00810

Gnomad4 FIN exome

AF:

0.00188

Gnomad4 NFE exome

AF:

0.00185

Gnomad4 OTH exome

AF:

0.00378

GnomAD4 genome

AF:

0.00325

AC:

481

AN:

147858

Hom.:

Cov.:

AF XY:

0.00314

AC XY:

226

AN XY:

71970

show subpopulations

Gnomad4 AFR

AF:

0.00963

Gnomad4 AMR

AF:

0.00134

Gnomad4 ASJ

AF:

0.00378

Gnomad4 EAS

AF:

0.00208

Gnomad4 SAS

AF:

0.00149

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000586

Gnomad4 OTH

AF:

0.00196

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2023

CACNA1A: PM4, BS1, BS2 -

CACNA1A-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 30, 2019

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). -

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