rs768950814

chr19-13208877-G-GGGTchr19-13208877-G-GGGTGGTchr19-13208877-G-GGGTGGTGGTchr19-13208877-G-GGGTGGTGGTGGT

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.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). Synonymous variant affecting the same amino acid position (i.e. P2220P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0080 (12 hom., cov: 31)
  • Exomes 𝑓: 0.0077 (39 hom.)
• Consequence: CACNA1A NM_001127222.2 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• 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-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=2, 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 GnomAd at 1199 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.6658_6659insACC	p.His2219dup	inframe_insertion	46/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6658_6659insACC	p.His2219dup	inframe_insertion	46/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes AF: 0.00797 AC: 1199 AN: 150444 Hom.: 12 Cov.: 31

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.: 12 AF XY: 0.00894 AC XY: 572 AN XY: 63980

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.: 39 Cov.: 74 AF XY: 0.00774 AC XY: 5008 AN XY: 646624

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.: 12 Cov.: 31 AF XY: 0.00766 AC XY: 563 AN XY: 73524

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.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 27, 2014	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2018	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 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	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

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

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 29, 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: rs768950814; hg19: chr19-13319691;