chr19-13208877-G-GGGT

Variant names:

• chr19-13208877-G-GGGT
• rs768950814
• NM_001127222.2:c.6658_6659insACC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BS1 BS2

The NM_001127222.2(CACNA1A):​c.6658_6659insACC​(p.His2219dup) variant causes a conservative inframe insertion change. The variant allele was found at a frequency of 0.00772 in 1,459,614 control chromosomes in the GnomAD database, including 51 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P2220P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0080 (12 hom., cov: 31)
  • Exomes 𝑓: 0.0077 (39 hom.)
• Consequence: CACNA1A NM_001127222.2 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• 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

Our verdict: Benign. The variant received -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001127222.2. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 19-13208877-G-GGGT is Benign according to our data. Variant chr19-13208877-G-GGGT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 210557.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1, Benign=5}.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00801 (1206/150552) while in subpopulation AFR AF = 0.0144 (589/40972). AF 95% confidence interval is 0.0134. There are 12 homozygotes in GnomAd4. There are 563 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position FAILED quality control check.
• BS2: High AC in GnomAd4 at 1206 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2	c.6658_6659insACC	p.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_6659insACC	p.His2219dup	conservative_inframe_insertion	Exon 46 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638029.1	c.6676_6677insACC	p.His2225dup	conservative_inframe_insertion	Exon 47 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7	c.6664_6665insACC	p.His2221dup	conservative_inframe_insertion	Exon 46 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1	c.6661_6662insACC	p.His2220dup	conservative_inframe_insertion	Exon 46 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1	c.6661_6662insACC	p.His2220dup	conservative_inframe_insertion	Exon 46 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1	c.6625_6626insACC	p.His2208dup	conservative_inframe_insertion	Exon 45 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1	c.6520_6521insACC	p.His2173dup	conservative_inframe_insertion	Exon 45 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1	c.6661_6662insACC	p.His2220dup	conservative_inframe_insertion	Exon 46 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1	c.6676_6677insACC	p.His2225dup	conservative_inframe_insertion	Exon 47 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1	c.6667_6668insACC	p.His2222dup	conservative_inframe_insertion	Exon 47 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1	c.6664_6665insACC	p.His2221dup	conservative_inframe_insertion	Exon 46 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1	c.6661_6662insACC	p.His2220dup	conservative_inframe_insertion	Exon 46 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000638009.2	c.6661_6662insACC	p.His2220dup	conservative_inframe_insertion	Exon 46 of 47	1		ENSP00000489913.1
CACNA1A	ENST00000637276.1	c.6625_6626insACC	p.His2208dup	conservative_inframe_insertion	Exon 45 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.1	n.*924_*925insACC		downstream_gene_variant		5		ENSP00000490190.2

Frequencies

GnomAD3 genomes AF: 0.00797 AC: 1199 AN: 150444 Hom.: 12 Cov.: 31

Gnomad AFR AF: 0.0143

Gnomad AMI AF: 0.00664

Gnomad AMR AF: 0.00482

Gnomad ASJ AF: 0.00665

Gnomad EAS AF: 0.00697

Gnomad SAS AF: 0.00886

Gnomad FIN AF: 0.000863

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.00585

Gnomad OTH AF: 0.0111

GnomAD2 exomes AF: 0.00868 AC: 1019 AN: 117448 AF XY: 0.00894

Gnomad AFR exome AF: 0.0172

Gnomad AMR exome AF: 0.00726

Gnomad ASJ exome AF: 0.0114

Gnomad EAS exome AF: 0.00947

Gnomad FIN exome AF: 0.00152

Gnomad NFE exome AF: 0.00596

Gnomad OTH exome AF: 0.00851

GnomAD4 exome AF: 0.00768 AC: 10058 AN: 1309062 Hom.: 39 Cov.: 74 AF XY: 0.00774 AC XY: 5008 AN XY: 646624

Gnomad4 AFR exome AF: 0.0184 AC: 532 AN: 28984

Gnomad4 AMR exome AF: 0.00696 AC: 236 AN: 33890

Gnomad4 ASJ exome AF: 0.0104 AC: 250 AN: 24010

Gnomad4 EAS exome AF: 0.00652 AC: 215 AN: 32960

Gnomad4 SAS exome AF: 0.0119 AC: 906 AN: 76330

Gnomad4 FIN exome AF: 0.00140 AC: 45 AN: 32216

Gnomad4 NFE exome AF: 0.00713 AC: 7281 AN: 1020678

Gnomad4 Remaining exome AF: 0.00994 AC: 544 AN: 54738

GnomAD4 genome AF: 0.00801 AC: 1206 AN: 150552 Hom.: 12 Cov.: 31 AF XY: 0.00766 AC XY: 563 AN XY: 73524

Gnomad4 AFR AF: 0.0144 AC: 0.0143757 AN: 0.0143757

Gnomad4 AMR AF: 0.00482 AC: 0.00481785 AN: 0.00481785

Gnomad4 ASJ AF: 0.00665 AC: 0.0066474 AN: 0.0066474

Gnomad4 EAS AF: 0.00719 AC: 0.00719137 AN: 0.00719137

Gnomad4 SAS AF: 0.00929 AC: 0.00929447 AN: 0.00929447

Gnomad4 FIN AF: 0.000863 AC: 0.000862565 AN: 0.000862565

Gnomad4 NFE AF: 0.00585 AC: 0.00585099 AN: 0.00585099

Gnomad4 OTH AF: 0.0110 AC: 0.0110048 AN: 0.0110048

Alfa AF: 0.00306 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:3

Jun 27, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 01, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

Jan 29, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1A: PM4:Supporting, BS1, BS2 -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 13, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Jul 07, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as 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

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=74/26	polymorphism

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs768950814; hg19: chr19-13319691;