rs749638821

Positions:

• chr19-13208877-GGAT-G
• chr19-13208877-GGAT-GGATGAT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BS1 BS2

The NM_001127222.2(CACNA1A):​c.6656_6658del​(p.His2219del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00156 in 1,373,696 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H2219HH) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00063 (1 hom., cov: 27)
  • Exomes 𝑓: 0.0017 (1 hom.)
• Consequence: CACNA1A NM_001127222.2 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 5.98

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 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-GGAT-G is Benign according to our data. Variant chr19-13208877-GGAT-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 377042.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2, Likely_benign=2}. Variant chr19-13208877-GGAT-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000631 (95/150506) while in subpopulation AMR AF= 0.000858 (13/15154). AF 95% confidence interval is 0.000507. There are 1 homozygotes in gnomad4. There are 53 alleles in male gnomad4 subpopulation. Median coverage is 27. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 95 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.6656_6658del	p.His2219del	inframe_deletion	46/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6656_6658del	p.His2219del	inframe_deletion	46/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes AF: 0.000618 AC: 93 AN: 150402 Hom.: 1 Cov.: 27

Gnomad AFR AF: 0.000489

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000859

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000598

Gnomad SAS AF: 0.000844

Gnomad FIN AF: 0.00115

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000578

Gnomad OTH AF: 0.000484

GnomAD3 exomes AF: 0.00226 AC: 265 AN: 117448 Hom.: 0 AF XY: 0.00219 AC XY: 140 AN XY: 63980

Gnomad AFR exome AF: 0.000904

Gnomad AMR exome AF: 0.00120

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00127

Gnomad SAS exome AF: 0.00236

Gnomad FIN exome AF: 0.00632

Gnomad NFE exome AF: 0.00282

Gnomad OTH exome AF: 0.00247

GnomAD4 exome AF: 0.00167 AC: 2044 AN: 1223190 Hom.: 1 AF XY: 0.00169 AC XY: 1023 AN XY: 604492

Gnomad4 AFR exome AF: 0.00147

Gnomad4 AMR exome AF: 0.00127

Gnomad4 ASJ exome AF: 0.000835

Gnomad4 EAS exome AF: 0.00107

Gnomad4 SAS exome AF: 0.00141

Gnomad4 FIN exome AF: 0.00173

Gnomad4 NFE exome AF: 0.00175

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.000631 AC: 95 AN: 150506 Hom.: 1 Cov.: 27 AF XY: 0.000721 AC XY: 53 AN XY: 73498

Gnomad4 AFR AF: 0.000537

Gnomad4 AMR AF: 0.000858

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000600

Gnomad4 SAS AF: 0.000845

Gnomad4 FIN AF: 0.00115

Gnomad4 NFE AF: 0.000578

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.0150 Hom.: 1

Bravo AF: 0.000586

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 30, 2016	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 07, 2023

This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 377042). 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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant, c.6659_6661del, results in the deletion of 1 amino acid(s) of the CACNA1A protein (p.His2220del), but otherwise preserves the integrity of the reading frame. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 03, 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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 18, 2020

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

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs749638821; hg19: chr19-13319691;