rs768950814

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_SupportingBP6BS1BS2

The NM_001127222.2(CACNA1A):c.6658_6659insACC(p.His2219dup) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.00772 in 1,459,614 control chromosomes in the GnomAD database, including 51 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0080 ( 12 hom., cov: 31)

Exomes 𝑓: 0.0077 ( 39 hom. )

Consequence

CACNA1A
NM_001127222.2 inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 5.98

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 -8 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001127222.2. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 19-13208877-G-GGGT is Benign according to our data. Variant chr19-13208877-G-GGGT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210557.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=5, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00801 (1206/150552) while in subpopulation AFR AF= 0.0144 (589/40972). AF 95% confidence interval is 0.0134. There are 12 homozygotes in gnomad4. There are 563 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1206 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 linkuse as main transcript	c.6658_6659insACC	p.His2219dup	inframe_insertion	46/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11 linkuse as main transcript	c.6658_6659insACC	p.His2219dup	inframe_insertion	46/47	1	NM_001127222.2	ENSP00000353362		O00555-8

Frequencies

GnomAD3 genomes

AF:

0.00797

AC:

1199

AN:

150444

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0143

Gnomad AMI

AF:

0.00664

Gnomad AMR

AF:

0.00482

Gnomad ASJ

AF:

0.00665

Gnomad EAS

AF:

0.00697

Gnomad SAS

AF:

0.00886

Gnomad FIN

AF:

0.000863

Gnomad MID

AF:

0.0223

Gnomad NFE

AF:

0.00585

Gnomad OTH

AF:

0.0111

GnomAD3 exomes

AF:

0.00868

AC:

1019

AN:

117448

Hom.:

AF XY:

0.00894

AC XY:

572

AN XY:

63980

show subpopulations

Gnomad AFR exome

AF:

0.0172

Gnomad AMR exome

AF:

0.00726

Gnomad ASJ exome

AF:

0.0114

Gnomad EAS exome

AF:

0.00947

Gnomad SAS exome

AF:

0.0145

Gnomad FIN exome

AF:

0.00152

Gnomad NFE exome

AF:

0.00596

Gnomad OTH exome

AF:

0.00851

GnomAD4 exome

AF:

0.00768

AC:

10058

AN:

1309062

Hom.:

Cov.:

AF XY:

0.00774

AC XY:

5008

AN XY:

646624

show subpopulations

Gnomad4 AFR exome

AF:

0.0184

Gnomad4 AMR exome

AF:

0.00696

Gnomad4 ASJ exome

AF:

0.0104

Gnomad4 EAS exome

AF:

0.00652

Gnomad4 SAS exome

AF:

0.0119

Gnomad4 FIN exome

AF:

0.00140

Gnomad4 NFE exome

AF:

0.00713

Gnomad4 OTH exome

AF:

0.00994

GnomAD4 genome

AF:

0.00801

AC:

1206

AN:

150552

Hom.:

Cov.:

AF XY:

0.00766

AC XY:

563

AN XY:

73524

show subpopulations

Gnomad4 AFR

AF:

0.0144

Gnomad4 AMR

AF:

0.00482

Gnomad4 ASJ

AF:

0.00665

Gnomad4 EAS

AF:

0.00719

Gnomad4 SAS

AF:

0.00929

Gnomad4 FIN

AF:

0.000863

Gnomad4 NFE

AF:

0.00585

Gnomad4 OTH

AF:

0.0110

Alfa

AF:

0.00306

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 27, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2018	- -
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	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided

Benign:4

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	Jul 01, 2024	CACNA1A: PM4:Supporting, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 13, 2017	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 07, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

CACNA1A-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 01, 2024

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