Genetic Variant NM_001127222.2:c.6654_6656dupCCA (chr19-13208879-A-ATGG) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_001127222.2(CACNA1A):c.6654_6656dupCCA(p.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 0.000679 in 1,453,796 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. H2219dup) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00067 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00068 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 0.00

Publications

4 publications found

Variant links:

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

CACNA1A links:

ENSG00000300728 (HGNC:):

ENSG00000300728 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001127222.2

BP6

Variant 19-13208879-A-ATGG is Benign according to our data. Variant chr19-13208879-A-ATGG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 419931.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000672 (100/148738) while in subpopulation SAS AF = 0.00309 (14/4532). AF 95% confidence interval is 0.00187. There are 0 homozygotes in GnomAd4. There are 48 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 100 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNA1A	NM_001127222.2	MANE Select	c.6654_6656dupCCA	p.His2219dup	disruptive_inframe_insertion	Exon 46 of 47	NP_001120694.1
CACNA1A	NM_001127221.2	MANE Plus Clinical	c.6657_6659dupCCA	p.His2220dup	disruptive_inframe_insertion	Exon 46 of 47	NP_001120693.1
CACNA1A	NM_023035.3		c.6672_6674dupCCA	p.His2225dup	disruptive_inframe_insertion	Exon 47 of 48	NP_075461.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNA1A	ENST00000360228.11	TSL:1 MANE Select	c.6654_6656dupCCA	p.His2219dup	disruptive_inframe_insertion	Exon 46 of 47	ENSP00000353362.5
CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.6657_6659dupCCA	p.His2220dup	disruptive_inframe_insertion	Exon 46 of 47	ENSP00000489913.1
CACNA1A	ENST00000638029.1	TSL:5	c.6672_6674dupCCA	p.His2225dup	disruptive_inframe_insertion	Exon 47 of 48	ENSP00000489829.1

Frequencies

GnomAD3 genomes

AF:

0.000673

AC:

100

AN:

148636

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000270

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00127

Gnomad ASJ

AF:

0.00205

Gnomad EAS

AF:

0.00122

Gnomad SAS

AF:

0.00309

Gnomad FIN

AF:

0.000200

Gnomad MID

AF:

0.00325

Gnomad NFE

AF:

0.000509

Gnomad OTH

AF:

0.00292

GnomAD2 exomes

AF:

0.00121

AC:

150

AN:

124082

AF XY:

0.00122

show subpopulations

Gnomad AFR exome

AF:

0.000322

Gnomad AMR exome

AF:

0.00221

Gnomad ASJ exome

AF:

0.00449

Gnomad EAS exome

AF:

0.000207

Gnomad FIN exome

AF:

0.000385

Gnomad NFE exome

AF:

0.000532

Gnomad OTH exome

AF:

0.00186

GnomAD4 exome

AF:

0.000680

AC:

887

AN:

1305058

Hom.:

Cov.:

AF XY:

0.000761

AC XY:

491

AN XY:

645194

show subpopulations

African (AFR)

AF:

0.000594

AC:

AN:

30302

American (AMR)

AF:

0.00186

AC:

AN:

34376

Ashkenazi Jewish (ASJ)

AF:

0.00433

AC:

102

AN:

23562

East Asian (EAS)

AF:

0.000263

AC:

AN:

34216

South Asian (SAS)

AF:

0.00189

AC:

145

AN:

76810

European-Finnish (FIN)

AF:

0.000338

AC:

AN:

32500

Middle Eastern (MID)

AF:

0.00188

AC:

AN:

4796

European-Non Finnish (NFE)

AF:

0.000464

AC:

471

AN:

1014130

Other (OTH)

AF:

0.00107

AC:

AN:

54366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.407

Heterozygous variant carriers

145

193

241

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000672

AC:

100

AN:

148738

Hom.:

Cov.:

AF XY:

0.000662

AC XY:

AN XY:

72496

show subpopulations

African (AFR)

AF:

0.000270

AC:

AN:

40794

American (AMR)

AF:

0.00127

AC:

AN:

15002

Ashkenazi Jewish (ASJ)

AF:

0.00205

AC:

AN:

3410

East Asian (EAS)

AF:

0.00122

AC:

AN:

4906

South Asian (SAS)

AF:

0.00309

AC:

AN:

4532

European-Finnish (FIN)

AF:

0.000200

AC:

AN:

10004

Middle Eastern (MID)

AF:

0.00350

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.000509

AC:

AN:

66852

Other (OTH)

AF:

0.00289

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.0

Mutation Taster

=74/26

polymorphism

(source)

Splicing

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over