rs776181081

chr19-13208877-GGATGGTGGT-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM4 BP6 BS2

The NM_001127222.2(CACNA1A):c.6650_6658del(p.His2217_His2219del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000353 in 1,459,904 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H2217H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00034 (1 hom.)
• Consequence: CACNA1A NM_001127222.2 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 7.16

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 Likely_benign. Variant got -3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001127222.2.
• BP6: Variant 19-13208877-GGATGGTGGT-G is Benign according to our data. Variant chr19-13208877-GGATGGTGGT-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 422029.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=2}.
• BS2: High AC in GnomAd at 69 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.6650_6658del	p.His2217_His2219del	inframe_deletion	46/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6650_6658del	p.His2217_His2219del	inframe_deletion	46/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes AF: 0.000459 AC: 69 AN: 150462 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000489

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000264

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00431

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000267

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000383 AC: 45 AN: 117448 Hom.: 0 AF XY: 0.000406 AC XY: 26 AN XY: 63980

Gnomad AFR exome AF: 0.000181

Gnomad AMR exome AF: 0.000139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000462

Gnomad SAS exome AF: 0.0000503

Gnomad FIN exome AF: 0.00479

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.000275

GnomAD4 exome AF: 0.000341 AC: 447 AN: 1309442 Hom.: 1 AF XY: 0.000326 AC XY: 211 AN XY: 646832

Gnomad4 AFR exome AF: 0.000138

Gnomad4 AMR exome AF: 0.000236

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000364

Gnomad4 SAS exome AF: 0.0000917

Gnomad4 FIN exome AF: 0.00450

Gnomad4 NFE exome AF: 0.000249

Gnomad4 OTH exome AF: 0.000310

GnomAD4 genome AF: 0.000459 AC: 69 AN: 150462 Hom.: 0 Cov.: 27 AF XY: 0.000586 AC XY: 43 AN XY: 73422

Gnomad4 AFR AF: 0.0000489

Gnomad4 AMR AF: 0.000264

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00431

Gnomad4 NFE AF: 0.000267

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000121 Hom.: 0

Bravo AF: 0.000249

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 01, 2017

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. This variant has not been reported in the literature in individuals with CACNA1A-related disease. ClinVar contains an entry for this variant (Variation ID: 422029). While this variant is present in population databases (rs776181081), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant, c.6653_6661delACCACCATC, results in the deletion of 3 amino acid(s) of the CACNA1A protein (p.His2218_His2220del), but otherwise preserves the integrity of the reading frame. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2023

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2020

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; In-frame deletion in a repetitive region with no known function; Has not been previously published as pathogenic or benign to our knowledge -

CACNA1A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 04, 2019

This variant is classified as likely 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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs776181081; hg19: chr19-13319691;