19-13207858-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG

Variant names:

• chr19-13207858-C-CCTGCTG
• rs16054
• NM_001127222.2:c.6970_6975dupCAGCAG

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_001127222.2(CACNA1A):​c.6970_6975dupCAGCAG​(p.Gln2324_Gln2325dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., cov: 0)
  • Exomes 𝑓: 0.0024 (23 hom.)
• Consequence: CACNA1A NM_001127222.2 conservative_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.00
• Publications: 10 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: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001127222.2
• BP6: Variant 19-13207858-C-CCTGCTG is Benign according to our data. Variant chr19-13207858-C-CCTGCTG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1285153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00273 (404/147904) while in subpopulation EAS AF = 0.0139 (67/4816). AF 95% confidence interval is 0.0112. There are 3 homozygotes in GnomAd4. There are 225 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 404 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.6970_6975dupCAGCAG	p.Gln2324_Gln2325dup	conservative_inframe_insertion	Exon 47 of 47	NP_001120694.1	O00555-8
	CACNA1A	NM_001127221.2	MANE Plus Clinical	c.*182_*187dupCAGCAG		3_prime_UTR	Exon 47 of 47	NP_001120693.1	O00555-3
	CACNA1A	NM_023035.3		c.6988_6993dupCAGCAG	p.Gln2330_Gln2331dup	conservative_inframe_insertion	Exon 48 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.6970_6975dupCAGCAG	p.Gln2324_Gln2325dup	conservative_inframe_insertion	Exon 47 of 47	ENSP00000353362.5	O00555-8
	CACNA1A	ENST00000638029.1	TSL:5	c.6988_6993dupCAGCAG	p.Gln2330_Gln2331dup	conservative_inframe_insertion	Exon 48 of 48	ENSP00000489829.1	A0A087WW63
	CACNA1A	ENST00000573710.7	TSL:5	c.6976_6981dupCAGCAG	p.Gln2326_Gln2327dup	conservative_inframe_insertion	Exon 47 of 47	ENSP00000460092.3	A0A1C7CYY9

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 404 AN: 147802 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.00249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00368

Gnomad ASJ AF: 0.000873

Gnomad EAS AF: 0.0141

Gnomad SAS AF: 0.00679

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0267

Gnomad NFE AF: 0.00176

Gnomad OTH AF: 0.00297

GnomAD2 exomes AF: 0.00527 AC: 274 AN: 52038 AF XY: 0.00509

Gnomad AFR exome AF: 0.00162

Gnomad AMR exome AF: 0.00605

Gnomad ASJ exome AF: 0.00147

Gnomad EAS exome AF: 0.0195

Gnomad FIN exome AF: 0.00181

Gnomad NFE exome AF: 0.00223

Gnomad OTH exome AF: 0.00526

GnomAD4 exome AF: 0.00244 AC: 3128 AN: 1283858 Hom.: 23 Cov.: 0 AF XY: 0.00256 AC XY: 1615 AN XY: 631904

African (AFR) AF: 0.00289 AC: 72 AN: 24930

American (AMR) AF: 0.00473 AC: 114 AN: 24096

Ashkenazi Jewish (ASJ) AF: 0.00138 AC: 30 AN: 21718

East Asian (EAS) AF: 0.0102 AC: 303 AN: 29576

South Asian (SAS) AF: 0.00678 AC: 445 AN: 65600

European-Finnish (FIN) AF: 0.00215 AC: 72 AN: 33418

Middle Eastern (MID) AF: 0.00533 AC: 20 AN: 3752

European-Non Finnish (NFE) AF: 0.00184 AC: 1893 AN: 1027626

Other (OTH) AF: 0.00337 AC: 179 AN: 53142

GnomAD4 genome AF: 0.00273 AC: 404 AN: 147904 Hom.: 3 Cov.: 0 AF XY: 0.00312 AC XY: 225 AN XY: 72002

African (AFR) AF: 0.00251 AC: 101 AN: 40206

American (AMR) AF: 0.00367 AC: 55 AN: 14968

Ashkenazi Jewish (ASJ) AF: 0.000873 AC: 3 AN: 3436

East Asian (EAS) AF: 0.0139 AC: 67 AN: 4816

South Asian (SAS) AF: 0.00680 AC: 32 AN: 4704

European-Finnish (FIN) AF: 0.00151 AC: 15 AN: 9952

Middle Eastern (MID) AF: 0.0254 AC: 7 AN: 276

European-Non Finnish (NFE) AF: 0.00177 AC: 118 AN: 66606

Other (OTH) AF: 0.00294 AC: 6 AN: 2044

Alfa AF: 0.00 Hom.: 195

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4310716:Developmental and epileptic encephalopathy, 42 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=81/19	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs16054; hg19: chr19-13318672; COSMIC: COSV64205776; COSMIC: COSV64205776;