19-13298647-GGCCCTCGCCCTC-GGCCCTCGCCCTCGCCCTC

Position:

• chr19-13298647-GGCCCTCGCCCTC-GGCCCTCGCCCTCGCCCTC

Variant summary

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

The NM_001127222.2(CACNA1A):​c.2980_2985dupGAGGGC​(p.Gly995_Pro996insGluGly) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 1,517,446 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 0.00059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: -1.91

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 19-13298647-G-GGCCCTC is Benign according to our data. Variant chr19-13298647-G-GGCCCTC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 421524.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=4}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000592 (90/152032) while in subpopulation AFR AF= 0.00181 (75/41518). AF 95% confidence interval is 0.00148. There are 0 homozygotes in gnomad4. There are 39 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 90 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.2980_2985dupGAGGGC	p.Gly995_Pro996insGluGly	conservative_inframe_insertion	19/47	ENST00000360228.11	NP_001120694.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1A	ENST00000360228.11	c.2980_2985dupGAGGGC	p.Gly995_Pro996insGluGly	conservative_inframe_insertion	19/47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.2992_2997dupGAGGGC	p.Gly999_Pro1000insGluGly	conservative_inframe_insertion	19/48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.2986_2991dupGAGGGC	p.Gly997_Pro998insGluGly	conservative_inframe_insertion	19/47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.2983_2988dupGAGGGC	p.Gly996_Pro997insGluGly	conservative_inframe_insertion	19/47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.2983_2988dupGAGGGC	p.Gly996_Pro997insGluGly	conservative_inframe_insertion	19/47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.2983_2988dupGAGGGC	p.Gly996_Pro997insGluGly	conservative_inframe_insertion	19/46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.2842_2847dupGAGGGC	p.Gly949_Pro950insGluGly	conservative_inframe_insertion	18/46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.2983_2988dupGAGGGC	p.Gly996_Pro997insGluGly	conservative_inframe_insertion	19/47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.2992_2997dupGAGGGC	p.Gly999_Pro1000insGluGly	conservative_inframe_insertion	19/48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.2983_2988dupGAGGGC	p.Gly996_Pro997insGluGly	conservative_inframe_insertion	19/48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.2986_2991dupGAGGGC	p.Gly997_Pro998insGluGly	conservative_inframe_insertion	19/47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.2983_2988dupGAGGGC	p.Gly996_Pro997insGluGly	conservative_inframe_insertion	19/47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.2983_2988dupGAGGGC	p.Gly996_Pro997insGluGly	conservative_inframe_insertion	19/47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.2983_2988dupGAGGGC	p.Gly996_Pro997insGluGly	conservative_inframe_insertion	19/46	5		ENSP00000489777.1

Frequencies

GnomAD3 genomes AF: 0.000592 AC: 90 AN: 151922 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000105 AC: 12 AN: 114332 Hom.: 0 AF XY: 0.0000962 AC XY: 6 AN XY: 62386

Gnomad AFR exome AF: 0.000375

Gnomad AMR exome AF: 0.000207

Gnomad ASJ exome AF: 0.000278

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000519

Gnomad FIN exome AF: 0.0000624

Gnomad NFE exome AF: 0.0000728

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000177 AC: 241 AN: 1365414 Hom.: 0 Cov.: 32 AF XY: 0.000169 AC XY: 114 AN XY: 673334

Gnomad4 AFR exome AF: 0.00127

Gnomad4 AMR exome AF: 0.000190

Gnomad4 ASJ exome AF: 0.000167

Gnomad4 EAS exome AF: 0.0000323

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000166

Gnomad4 OTH exome AF: 0.000142

GnomAD4 genome AF: 0.000592 AC: 90 AN: 152032 Hom.: 0 Cov.: 33 AF XY: 0.000525 AC XY: 39 AN XY: 74306

Gnomad4 AFR AF: 0.00181

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 21, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 15, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 23, 2014	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	CACNA1A: BS1, BS2 -

Developmental and epileptic encephalopathy, 42 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

May 08, 2018

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 03, 2019

This alteration is classified as 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, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2021

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;