19-13208877-G-GGGTGGTGGTGGTGGTGGT

Variant names:

• chr19-13208877-G-GGGTGGTGGTGGTGGTGGT
• NM_001127222.2:c.6658_6659insACCACCACCACCACCACC

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_001127222.2(CACNA1A):​c.6658_6659insACCACCACCACCACCACC​(p.His2214_His2219dup) variant causes a conservative inframe insertion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000015 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1A NM_001127222.2 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001127222.2.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6658_6659insACCACCACCACCACCACC	p.His2214_His2219dup	conservative_inframe_insertion	Exon 46 of 47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6658_6659insACCACCACCACCACCACC	p.His2214_His2219dup	conservative_inframe_insertion	Exon 46 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6676_6677insACCACCACCACCACCACC	p.His2220_His2225dup	conservative_inframe_insertion	Exon 47 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6664_6665insACCACCACCACCACCACC	p.His2216_His2221dup	conservative_inframe_insertion	Exon 46 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6661_6662insACCACCACCACCACCACC	p.His2215_His2220dup	conservative_inframe_insertion	Exon 46 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6661_6662insACCACCACCACCACCACC	p.His2215_His2220dup	conservative_inframe_insertion	Exon 46 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6625_6626insACCACCACCACCACCACC	p.His2203_His2208dup	conservative_inframe_insertion	Exon 45 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6520_6521insACCACCACCACCACCACC	p.His2168_His2173dup	conservative_inframe_insertion	Exon 45 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6661_6662insACCACCACCACCACCACC	p.His2215_His2220dup	conservative_inframe_insertion	Exon 46 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6676_6677insACCACCACCACCACCACC	p.His2220_His2225dup	conservative_inframe_insertion	Exon 47 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6667_6668insACCACCACCACCACCACC	p.His2217_His2222dup	conservative_inframe_insertion	Exon 47 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6664_6665insACCACCACCACCACCACC	p.His2216_His2221dup	conservative_inframe_insertion	Exon 46 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6661_6662insACCACCACCACCACCACC	p.His2215_His2220dup	conservative_inframe_insertion	Exon 46 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6661_6662insACCACCACCACCACCACC	p.His2215_His2220dup	conservative_inframe_insertion	Exon 46 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6625_6626insACCACCACCACCACCACC	p.His2203_His2208dup	conservative_inframe_insertion	Exon 45 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*924_*925insACCACCACCACCACCACC		downstream_gene_variant		5		ENSP00000490190.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000153 AC: 2 AN: 1309460 Hom.: 0 Cov.: 74 AF XY: 0.00000155 AC XY: 1 AN XY: 646842

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000196

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Mar 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant has not been reported in the literature in individuals affected with CACNA1A-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.6661_6662insACCACCACCACCACCACC, results in the insertion of 6 amino acid(s) of the CACNA1A protein (p.His2215_His2220dup), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-13319691;