chr19-13208877-G-GGGT

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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).

• 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

Verdict is Benign. Variant got -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: {Likely_benign=1, Benign=5, Uncertain_significance=1}.
• 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• 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

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

GnomAD3 exomes AF: 0.00868 AC: 1019 AN: 117448 Hom.: 12 AF XY: 0.00894 AC XY: 572 AN XY: 63980

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 SAS exome AF: 0.0145

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

Gnomad4 AMR exome AF: 0.00696

Gnomad4 ASJ exome AF: 0.0104

Gnomad4 EAS exome AF: 0.00652

Gnomad4 SAS exome AF: 0.0119

Gnomad4 FIN exome AF: 0.00140

Gnomad4 NFE exome AF: 0.00713

Gnomad4 OTH exome AF: 0.00994

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

Gnomad4 AMR AF: 0.00482

Gnomad4 ASJ AF: 0.00665

Gnomad4 EAS AF: 0.00719

Gnomad4 SAS AF: 0.00929

Gnomad4 FIN AF: 0.000863

Gnomad4 NFE AF: 0.00585

Gnomad4 OTH AF: 0.0110

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

Mar 01, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

not provided Benign:4

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

- -

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 -

Jan 29, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

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

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;