19-13208879-ATGGTGGTGGTGGTGGTGG-ATGGTGGTGG

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP6BS2

The NM_001127222.2(CACNA1A):c.6648_6656delCCACCACCA(p.His2217_His2219del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000798 in 1,454,150 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000083 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 8.26

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

BP6

Variant 19-13208879-ATGGTGGTGG-A is Benign according to our data. Variant chr19-13208879-ATGGTGGTGG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 422030.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.6648_6656delCCACCACCA	p.His2217_His2219del	disruptive_inframe_deletion	Exon 46 of 47	ENST00000360228.11	NP_001120694.1	O00555-8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1A	ENST00000360228.11 link	c.6648_6656delCCACCACCA	p.His2217_His2219del	disruptive_inframe_deletion	Exon 46 of 47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 link	c.6666_6674delCCACCACCA	p.His2223_His2225del	disruptive_inframe_deletion	Exon 47 of 48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.6654_6662delCCACCACCA	p.His2219_His2221del	disruptive_inframe_deletion	Exon 46 of 47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.6651_6659delCCACCACCA	p.His2218_His2220del	disruptive_inframe_deletion	Exon 46 of 47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 link	c.6651_6659delCCACCACCA	p.His2218_His2220del	disruptive_inframe_deletion	Exon 46 of 47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 link	c.6615_6623delCCACCACCA	p.His2206_His2208del	disruptive_inframe_deletion	Exon 45 of 46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 link	c.6510_6518delCCACCACCA	p.His2171_His2173del	disruptive_inframe_deletion	Exon 45 of 46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636389.1 link	c.6651_6659delCCACCACCA	p.His2218_His2220del	disruptive_inframe_deletion	Exon 46 of 47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 link	c.6666_6674delCCACCACCA	p.His2223_His2225del	disruptive_inframe_deletion	Exon 47 of 48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000636549.1 link	c.6657_6665delCCACCACCA	p.His2220_His2222del	disruptive_inframe_deletion	Exon 47 of 48	5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 link	c.6654_6662delCCACCACCA	p.His2219_His2221del	disruptive_inframe_deletion	Exon 46 of 47	5		ENSP00000489715.1	A0A1B0GTI4
CACNA1A	ENST00000635895.1 link	c.6651_6659delCCACCACCA	p.His2218_His2220del	disruptive_inframe_deletion	Exon 46 of 47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 link	c.6651_6659delCCACCACCA	p.His2218_His2220del	disruptive_inframe_deletion	Exon 46 of 47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 link	c.6615_6623delCCACCACCA	p.His2206_His2208del	disruptive_inframe_deletion	Exon 45 of 46	5		ENSP00000489777.1	O00555-5
CACNA1A	ENST00000636768.1 link	n.914_922delCCACCACCA		downstream_gene_variant		5		ENSP00000490190.2	A0A1B0GUP3

Frequencies

GnomAD3 genomes

AF:

0.0000538

AC:

AN:

148640

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000120

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000806

AC:

AN:

124082

Hom.:

AF XY:

0.0000890

AC XY:

AN XY:

67406

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000451

Gnomad ASJ exome

AF:

0.000132

Gnomad EAS exome

AF:

0.000103

Gnomad SAS exome

AF:

0.0000484

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000102

Gnomad OTH exome

AF:

0.000265

GnomAD4 exome

AF:

0.0000827

AC:

108

AN:

1305510

Hom.:

AF XY:

0.0000651

AC XY:

AN XY:

645420

show subpopulations

Gnomad4 AFR exome

AF:

0.0000660

Gnomad4 AMR exome

AF:

0.0000582

Gnomad4 ASJ exome

AF:

0.0000424

Gnomad4 EAS exome

AF:

0.0000584

Gnomad4 SAS exome

AF:

0.0000260

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000897

Gnomad4 OTH exome

AF:

0.000147

GnomAD4 genome

AF:

0.0000538

AC:

AN:

148640

Hom.:

Cov.:

AF XY:

0.0000553

AC XY:

AN XY:

72384

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000120

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Nov 30, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 26, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CACNA1A-related disorder

Uncertain:1

Dec 22, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CACNA1A c.6648_6656del9 variant is predicted to result in an in-frame deletion (p.His2217_His2219del). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.013% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-13319693-ATGGTGGTGG-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases

Benign:1

Oct 24, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

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