rs770368215

chr19-13208877-GGATGGTGGTGGT-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM4 PP3 BP6 BS2

The NM_001127222.2(CACNA1A):c.6647_6658del(p.His2216_His2219del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000258 in 1,460,020 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. H2216H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 8.26

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 -2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001127222.2.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP6: Variant 19-13208877-GGATGGTGGTGGT-G is Benign according to our data. Variant chr19-13208877-GGATGGTGGTGGT-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 421166.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• 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.6647_6658del	p.His2216_His2219del	inframe_deletion	46/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.6647_6658del	p.His2216_His2219del	inframe_deletion	46/47	1	NM_001127222.2

Frequencies

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

Gnomad AFR AF: 0.000171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000199

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000252

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000315 AC: 37 AN: 117448 Hom.: 0 AF XY: 0.000297 AC XY: 19 AN XY: 63980

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000277

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000115

Gnomad SAS exome AF: 0.000251

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000542

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000267 AC: 349 AN: 1309450 Hom.: 0 AF XY: 0.000260 AC XY: 168 AN XY: 646838

Gnomad4 AFR exome AF: 0.000138

Gnomad4 AMR exome AF: 0.000177

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000182

Gnomad4 SAS exome AF: 0.000327

Gnomad4 FIN exome AF: 0.0000621

Gnomad4 NFE exome AF: 0.000285

Gnomad4 OTH exome AF: 0.000274

GnomAD4 genome AF: 0.000179 AC: 27 AN: 150570 Hom.: 0 Cov.: 27 AF XY: 0.000163 AC XY: 12 AN XY: 73540

Gnomad4 AFR AF: 0.000171

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000200

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000252

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000282 Hom.: 0

Bravo AF: 0.000185

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 07, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2017	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 11, 2017

In summary, this variant has uncertain impact on CACNA1A function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acids is currently unknown. This variant has not been reported in the literature in individuals with a CACNA1A-related disease. ClinVar contains an entry for this variant (Variation ID: 421166). While this variant is present in population databases (rs770368215), the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant, c.6650_6661delACCACCACCATC, results in the deletion of 4 amino acid(s) of the CACNA1A protein (p.His2217_His2220del), but otherwise preserves the integrity of the reading frame. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 11, 2019

- -

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: rs770368215; hg19: chr19-13319691;