19-13208877-G-GGGTGGTGGT

Variant names:

• chr19-13208877-G-GGGTGGTGGT
• rs768950814
• NM_001127222.2:c.6658_6659insACCACCACC

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_001127222.2(CACNA1A):​c.6658_6659insACCACCACC​(p.His2217_His2219dup) variant causes a conservative inframe insertion change. The variant allele was found at a frequency of 0.00000665 in 150,462 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P2220P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1A NM_001127222.2 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.98
• Publications: 2 publications found

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]

CACNA1A Gene-Disease associations (from GenCC):

• episodic ataxia type 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, Orphanet
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
• developmental and epileptic encephalopathy, 42

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• migraine, familial hemiplegic, 1

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• spinocerebellar ataxia type 6

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• benign paroxysmal torticollis of infancy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial or sporadic hemiplegic migraine

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Lennox-Gastaut syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000300728 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_001127222.2.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127222.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1A	NM_001127222.2	MANE Select	c.6658_6659insACCACCACC	p.His2217_His2219dup	conservative_inframe_insertion	Exon 46 of 47	NP_001120694.1	O00555-8
	CACNA1A	NM_001127221.2	MANE Plus Clinical	c.6661_6662insACCACCACC	p.His2218_His2220dup	conservative_inframe_insertion	Exon 46 of 47	NP_001120693.1	O00555-3
	CACNA1A	NM_023035.3		c.6676_6677insACCACCACC	p.His2223_His2225dup	conservative_inframe_insertion	Exon 47 of 48	NP_075461.2	A0A087WW63

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1A	ENST00000360228.11	TSL:1 MANE Select	c.6658_6659insACCACCACC	p.His2217_His2219dup	conservative_inframe_insertion	Exon 46 of 47	ENSP00000353362.5	O00555-8
	CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.6661_6662insACCACCACC	p.His2218_His2220dup	conservative_inframe_insertion	Exon 46 of 47	ENSP00000489913.1	O00555-3
	CACNA1A	ENST00000638029.1	TSL:5	c.6676_6677insACCACCACC	p.His2223_His2225dup	conservative_inframe_insertion	Exon 47 of 48	ENSP00000489829.1	A0A087WW63

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150462 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000122 AC: 16 AN: 1309458 Hom.: 0 Cov.: 74 AF XY: 0.0000201 AC XY: 13 AN XY: 646842

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 28996

American (AMR) AF: 0.00 AC: 0 AN: 33894

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24028

East Asian (EAS) AF: 0.00 AC: 0 AN: 32968

South Asian (SAS) AF: 0.0000524 AC: 4 AN: 76342

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5258

European-Non Finnish (NFE) AF: 0.0000118 AC: 12 AN: 1021000

Other (OTH) AF: 0.00 AC: 0 AN: 54756

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000144173), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150462 Hom.: 0 Cov.: 31 AF XY: 0.0000136 AC XY: 1 AN XY: 73422

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 40868

American (AMR) AF: 0.00 AC: 0 AN: 15138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5018

South Asian (SAS) AF: 0.00 AC: 0 AN: 4740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67518

Other (OTH) AF: 0.00 AC: 0 AN: 2068

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.0
Mutation Taster		=74/26	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs768950814; hg19: chr19-13319691; COSMIC: COSV100803018; COSMIC: COSV100803018;