19-13208879-A-ATGGTGG

Variant names:

• chr19-13208879-A-ATGGTGG
• rs759331923
• NM_001127222.2:c.6651_6656dupCCACCA

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS2

The NM_001127222.2(CACNA1A):​c.6651_6656dupCCACCA​(p.His2218_His2219dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,454,076 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H2219dup) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (1 hom., cov: 31)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00
• Publications: 4 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: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

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

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

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

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• 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: Benign. The variant received -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001127222.2
• BP6: Variant 19-13208879-A-ATGGTGG is Benign according to our data. Variant chr19-13208879-A-ATGGTGG is described in ClinVar as Likely_benign. ClinVar VariationId is 506403.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 18 AD gene.

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.6651_6656dupCCACCA	p.His2218_His2219dup	disruptive_inframe_insertion	Exon 46 of 47	NP_001120694.1
	CACNA1A	NM_001127221.2	MANE Plus Clinical	c.6654_6659dupCCACCA	p.His2219_His2220dup	disruptive_inframe_insertion	Exon 46 of 47	NP_001120693.1
	CACNA1A	NM_023035.3		c.6669_6674dupCCACCA	p.His2224_His2225dup	disruptive_inframe_insertion	Exon 47 of 48	NP_075461.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1A	ENST00000360228.11	TSL:1 MANE Select	c.6651_6656dupCCACCA	p.His2218_His2219dup	disruptive_inframe_insertion	Exon 46 of 47	ENSP00000353362.5
	CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.6654_6659dupCCACCA	p.His2219_His2220dup	disruptive_inframe_insertion	Exon 46 of 47	ENSP00000489913.1
	CACNA1A	ENST00000638029.1	TSL:5	c.6669_6674dupCCACCA	p.His2224_His2225dup	disruptive_inframe_insertion	Exon 47 of 48	ENSP00000489829.1

Frequencies

GnomAD3 genomes AF: 0.000121 AC: 18 AN: 148640 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.0000492

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000133

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000441

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000179

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000887 AC: 11 AN: 124082 AF XY: 0.0000890

Gnomad AFR exome AF: 0.000161

Gnomad AMR exome AF: 0.0000902

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000146 AC: 191 AN: 1305436 Hom.: 0 Cov.: 31 AF XY: 0.000139 AC XY: 90 AN XY: 645392

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

African (AFR) AF: 0.0000660 AC: 2 AN: 30304

American (AMR) AF: 0.0000873 AC: 3 AN: 34382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23566

East Asian (EAS) AF: 0.00 AC: 0 AN: 34222

South Asian (SAS) AF: 0.0000781 AC: 6 AN: 76830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4798

European-Non Finnish (NFE) AF: 0.000164 AC: 166 AN: 1014450

Other (OTH) AF: 0.000257 AC: 14 AN: 54384

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000121 AC: 18 AN: 148640 Hom.: 1 Cov.: 31 AF XY: 0.0000553 AC XY: 4 AN XY: 72384

African (AFR) AF: 0.0000492 AC: 2 AN: 40684

American (AMR) AF: 0.000133 AC: 2 AN: 14984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3412

East Asian (EAS) AF: 0.00 AC: 0 AN: 4922

South Asian (SAS) AF: 0.000441 AC: 2 AN: 4536

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.000179 AC: 12 AN: 66860

Other (OTH) AF: 0.00 AC: 0 AN: 2056

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
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: rs759331923; hg19: chr19-13319693;