19-13208879-ATGGTGGTGGTGGTGGTGG-ATGGTGGTGGTGG

Variant names:

• chr19-13208879-ATGGTGG-A
• rs759331923
• NM_001127222.2:c.6651_6656delCCACCA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_001127222.2(CACNA1A):​c.6651_6656delCCACCA​(p.His2218_His2219del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000853 in 1,454,202 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000081 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• 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 -5 ACMG points.

• BP6: Variant 19-13208879-ATGGTGG-A is Benign according to our data. Variant chr19-13208879-ATGGTGG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1175508.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6651_6656delCCACCA	p.His2218_His2219del	disruptive_inframe_deletion	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.6651_6656delCCACCA	p.His2218_His2219del	disruptive_inframe_deletion	Exon 46 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6669_6674delCCACCA	p.His2224_His2225del	disruptive_inframe_deletion	Exon 47 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6657_6662delCCACCA	p.His2220_His2221del	disruptive_inframe_deletion	Exon 46 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6654_6659delCCACCA	p.His2219_His2220del	disruptive_inframe_deletion	Exon 46 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6654_6659delCCACCA	p.His2219_His2220del	disruptive_inframe_deletion	Exon 46 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6618_6623delCCACCA	p.His2207_His2208del	disruptive_inframe_deletion	Exon 45 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6513_6518delCCACCA	p.His2172_His2173del	disruptive_inframe_deletion	Exon 45 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6654_6659delCCACCA	p.His2219_His2220del	disruptive_inframe_deletion	Exon 46 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6669_6674delCCACCA	p.His2224_His2225del	disruptive_inframe_deletion	Exon 47 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6660_6665delCCACCA	p.His2221_His2222del	disruptive_inframe_deletion	Exon 47 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6657_6662delCCACCA	p.His2220_His2221del	disruptive_inframe_deletion	Exon 46 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6654_6659delCCACCA	p.His2219_His2220del	disruptive_inframe_deletion	Exon 46 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6654_6659delCCACCA	p.His2219_His2220del	disruptive_inframe_deletion	Exon 46 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6618_6623delCCACCA	p.His2207_His2208del	disruptive_inframe_deletion	Exon 45 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*917_*922delCCACCA		downstream_gene_variant		5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.0000807 AC: 12 AN: 148640 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000737

Gnomad AMI AF: 0.00114

Gnomad AMR AF: 0.0000667

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000105

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000858 AC: 112 AN: 1305460 Hom.: 0 AF XY: 0.0000976 AC XY: 63 AN XY: 645394

Gnomad4 AFR exome AF: 0.0000330

Gnomad4 AMR exome AF: 0.0000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000260

Gnomad4 FIN exome AF: 0.0000308

Gnomad4 NFE exome AF: 0.0000996

Gnomad4 OTH exome AF: 0.0000919

GnomAD4 genome AF: 0.0000807 AC: 12 AN: 148742 Hom.: 0 Cov.: 31 AF XY: 0.0000966 AC XY: 7 AN XY: 72498

Gnomad4 AFR AF: 0.0000735

Gnomad4 AMR AF: 0.0000666

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000105

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Aug 07, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals with CACNA1A-related conditions. 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. This variant, c.6654_6659del, results in the deletion of 2 amino acid(s) of the CACNA1A protein (p.His2219_His2220del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. -

Inborn genetic diseases Benign:1

Sep 08, 2017

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 15, 2023

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

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: rs759331923; hg19: chr19-13319693;