19-13298647-GGCCCTCGCCCTC-GGCCCTC

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BS1 BS2

The NM_001127222.2(CACNA1A):c.2980_2985del(p.Glu994_Gly995del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000546 in 1,517,422 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00057 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.39

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 -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001127222.2.
• BP6: Variant 19-13298647-GGCCCTC-G is Benign according to our data. Variant chr19-13298647-GGCCCTC-G is described in ClinVar as [Likely_benign]. Clinvar id is 422039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000316 (48/152032) while in subpopulation EAS AF= 0.000582 (3/5152). AF 95% confidence interval is 0.000381. There are 0 homozygotes in gnomad4. There are 25 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1A	NM_001127222.2	c.2980_2985del	p.Glu994_Gly995del	inframe_deletion	19/47	ENST00000360228.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2980_2985del	p.Glu994_Gly995del	inframe_deletion	19/47	1	NM_001127222.2

Frequencies

GnomAD3 genomes AF: 0.000329 AC: 50 AN: 151922 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000967

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000950

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000245 AC: 28 AN: 114332 Hom.: 0 AF XY: 0.000256 AC XY: 16 AN XY: 62386

Gnomad AFR exome AF: 0.000751

Gnomad AMR exome AF: 0.0000518

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000519

Gnomad FIN exome AF: 0.0000624

Gnomad NFE exome AF: 0.000340

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000572 AC: 781 AN: 1365390 Hom.: 0 AF XY: 0.000575 AC XY: 387 AN XY: 673324

Gnomad4 AFR exome AF: 0.000109

Gnomad4 AMR exome AF: 0.0000634

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000647

Gnomad4 SAS exome AF: 0.000602

Gnomad4 FIN exome AF: 0.000124

Gnomad4 NFE exome AF: 0.000631

Gnomad4 OTH exome AF: 0.000889

GnomAD4 genome AF: 0.000316 AC: 48 AN: 152032 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74306

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000582

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000950

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.000474

Bravo AF: 0.000291

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	CACNA1A: BP3 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 25, 2021

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2022

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. -

CACNA1A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 21, 2023

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: rs764399373; hg19: chr19-13409461;