NM_001127222.2:c.6658_6659insACCACC

Variant names:

• chr19-13208877-G-GGGTGGT
• rs768950814
• NM_001127222.2:c.6658_6659insACCACC

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM4 BP6 BS1 BS2

The NM_001127222.2(CACNA1A):​c.6658_6659insACCACC​(p.His2218_His2219dup) variant causes a conservative inframe insertion change. The variant allele was found at a frequency of 0.000179 in 150,462 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00024 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: CACNA1A NM_001127222.2 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• 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: Benign. The variant received -7 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_001127222.2.
• BP6: Variant 19-13208877-G-GGGTGGT is Benign according to our data. Variant chr19-13208877-G-GGGTGGT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1754740.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000179 (27/150462) while in subpopulation SAS AF = 0.00105 (5/4740). AF 95% confidence interval is 0.000415. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 27 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.6658_6659insACCACC	p.His2218_His2219dup	conservative_inframe_insertion	Exon 46 of 47	NP_001120694.1	O00555-8
	CACNA1A	NM_001127221.2	MANE Plus Clinical	c.6661_6662insACCACC	p.His2219_His2220dup	conservative_inframe_insertion	Exon 46 of 47	NP_001120693.1	O00555-3
	CACNA1A	NM_023035.3		c.6676_6677insACCACC	p.His2224_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_6659insACCACC	p.His2218_His2219dup	conservative_inframe_insertion	Exon 46 of 47	ENSP00000353362.5	O00555-8
	CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.6661_6662insACCACC	p.His2219_His2220dup	conservative_inframe_insertion	Exon 46 of 47	ENSP00000489913.1	O00555-3
	CACNA1A	ENST00000638029.1	TSL:5	c.6676_6677insACCACC	p.His2224_His2225dup	conservative_inframe_insertion	Exon 47 of 48	ENSP00000489829.1	A0A087WW63

Frequencies

GnomAD3 genomes AF: 0.000179 AC: 27 AN: 150462 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000399

Gnomad SAS AF: 0.00105

Gnomad FIN AF: 0.0000958

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000163

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000315 AC: 37 AN: 117448 AF XY: 0.000453

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000231

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000130

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000242 AC: 317 AN: 1309430 Hom.: 3 Cov.: 74 AF XY: 0.000263 AC XY: 170 AN XY: 646832

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

African (AFR) AF: 0.000207 AC: 6 AN: 28996

American (AMR) AF: 0.0000295 AC: 1 AN: 33894

Ashkenazi Jewish (ASJ) AF: 0.0000416 AC: 1 AN: 24028

East Asian (EAS) AF: 0.000121 AC: 4 AN: 32968

South Asian (SAS) AF: 0.00132 AC: 101 AN: 76338

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

Middle Eastern (MID) AF: 0.000190 AC: 1 AN: 5258

European-Non Finnish (NFE) AF: 0.000191 AC: 195 AN: 1020978

Other (OTH) AF: 0.000146 AC: 8 AN: 54754

⚠️ 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: 0.000179 AC: 27 AN: 150462 Hom.: 0 Cov.: 31 AF XY: 0.000163 AC XY: 12 AN XY: 73422

African (AFR) AF: 0.000196 AC: 8 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: 0.000399 AC: 2 AN: 5018

South Asian (SAS) AF: 0.00105 AC: 5 AN: 4740

European-Finnish (FIN) AF: 0.0000958 AC: 1 AN: 10434

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

European-Non Finnish (NFE) AF: 0.000163 AC: 11 AN: 67518

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

Alfa AF: 0.000161 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 (1)
-	-	1	Inborn genetic diseases (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;