19-13208877-G-GGGTGGT

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM4 BP6 BS1 BS2

The NM_001127222.2(CACNA1A):c.6658_6659insACCACC(p.His2218_His2219dup) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.000179 in 150,462 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00024 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1A NM_001127222.2 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• 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 -7 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001127222.2.
• BP6: Variant 19-13208877-G-GGGTGGT is Benign according to our data. Variant chr19-13208877-G-GGGTGGT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1754740.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000179 (27/150462) while in subpopulation SAS AF= 0.00105 (5/4740). AF 95% confidence interval is 0.000415. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.6658_6659insACCACC	p.His2218_His2219dup	inframe_insertion	46/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6658_6659insACCACC	p.His2218_His2219dup	inframe_insertion	46/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes AF: 0.000179 AC: 27 AN: 150462 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000399

Gnomad SAS AF: 0.00105

Gnomad FIN AF: 0.0000958

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000163

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000315 AC: 37 AN: 117448 Hom.: 0 AF XY: 0.000453 AC XY: 29 AN XY: 63980

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000231

Gnomad SAS exome AF: 0.00146

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000130

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000242 AC: 317 AN: 1309430 Hom.: 3 Cov.: 74 AF XY: 0.000263 AC XY: 170 AN XY: 646832

Gnomad4 AFR exome AF: 0.000207

Gnomad4 AMR exome AF: 0.0000295

Gnomad4 ASJ exome AF: 0.0000416

Gnomad4 EAS exome AF: 0.000121

Gnomad4 SAS exome AF: 0.00132

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000191

Gnomad4 OTH exome AF: 0.000146

GnomAD4 genome AF: 0.000179 AC: 27 AN: 150462 Hom.: 0 Cov.: 31 AF XY: 0.000163 AC XY: 12 AN XY: 73422

Gnomad4 AFR AF: 0.000196

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000399

Gnomad4 SAS AF: 0.00105

Gnomad4 FIN AF: 0.0000958

Gnomad4 NFE AF: 0.000163

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000161 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

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

Mar 10, 2020

This variant has not been reported in the literature in individuals with CACNA1A-related conditions. While this variant is present in population databases (rs768950814), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant, c.6661_6662insACCACC, results in the insertion of 2 amino acid(s) to the CACNA1A protein (p.His2219_His2220dup), but otherwise preserves the integrity of the reading frame. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2017

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

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;