dbSNP rs768950814: CACNA1A:p.His2219dup (chr19-13208877-G-GGGT) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PM4_SupportingBP6BS1BS2

The NM_001127222.2(CACNA1A):c.6658_6659insACC(p.His2219dup) variant causes a conservative inframe insertion change. The variant allele was found at a frequency of 0.00772 in 1,459,614 control chromosomes in the GnomAD database, including 51 homozygotes. 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 0.0080 ( 12 hom., cov: 31)

Exomes 𝑓: 0.0077 ( 39 hom. )

Consequence

CACNA1A
NM_001127222.2 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: 5.98

Publications

2 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: 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

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 -8 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001127222.2. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 19-13208877-G-GGGT is Benign according to our data. Variant chr19-13208877-G-GGGT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210557.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00801 (1206/150552) while in subpopulation AFR AF = 0.0144 (589/40972). AF 95% confidence interval is 0.0134. There are 12 homozygotes in GnomAd4. There are 563 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 1206 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	UniProt
CACNA1A	NM_001127222.2	MANE Select	c.6658_6659insACC	p.His2219dup	conservative_inframe_insertion	Exon 46 of 47	NP_001120694.1	O00555-8
CACNA1A	NM_001127221.2	MANE Plus Clinical	c.6661_6662insACC	p.His2220dup	conservative_inframe_insertion	Exon 46 of 47	NP_001120693.1	O00555-3
CACNA1A	NM_023035.3		c.6676_6677insACC	p.His2225dup	conservative_inframe_insertion	Exon 47 of 48	NP_075461.2	A0A087WW63

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CACNA1A	ENST00000360228.11	TSL:1 MANE Select	c.6658_6659insACC	p.His2219dup	conservative_inframe_insertion	Exon 46 of 47	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.6661_6662insACC	p.His2220dup	conservative_inframe_insertion	Exon 46 of 47	ENSP00000489913.1	O00555-3
CACNA1A	ENST00000638029.1	TSL:5	c.6676_6677insACC	p.His2225dup	conservative_inframe_insertion	Exon 47 of 48	ENSP00000489829.1	A0A087WW63

Frequencies

GnomAD3 genomes

AF:

0.00797

AC:

1199

AN:

150444

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0143

Gnomad AMI

AF:

0.00664

Gnomad AMR

AF:

0.00482

Gnomad ASJ

AF:

0.00665

Gnomad EAS

AF:

0.00697

Gnomad SAS

AF:

0.00886

Gnomad FIN

AF:

0.000863

Gnomad MID

AF:

0.0223

Gnomad NFE

AF:

0.00585

Gnomad OTH

AF:

0.0111

GnomAD2 exomes

AF:

0.00868

AC:

1019

AN:

117448

AF XY:

0.00894

show subpopulations

Gnomad AFR exome

AF:

0.0172

Gnomad AMR exome

AF:

0.00726

Gnomad ASJ exome

AF:

0.0114

Gnomad EAS exome

AF:

0.00947

Gnomad FIN exome

AF:

0.00152

Gnomad NFE exome

AF:

0.00596

Gnomad OTH exome

AF:

0.00851

GnomAD4 exome

AF:

0.00768

AC:

10058

AN:

1309062

Hom.:

Cov.:

AF XY:

0.00774

AC XY:

5008

AN XY:

646624

show subpopulations

African (AFR)

AF:

0.0184

AC:

532

AN:

28984

American (AMR)

AF:

0.00696

AC:

236

AN:

33890

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

250

AN:

24010

East Asian (EAS)

AF:

0.00652

AC:

215

AN:

32960

South Asian (SAS)

AF:

0.0119

AC:

906

AN:

76330

European-Finnish (FIN)

AF:

0.00140

AC:

AN:

32216

Middle Eastern (MID)

AF:

0.00932

AC:

AN:

5256

European-Non Finnish (NFE)

AF:

0.00713

AC:

7281

AN:

1020678

Other (OTH)

AF:

0.00994

AC:

544

AN:

54738

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.405

Heterozygous variant carriers

478

957

1435

1914

2392

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

316

632

948

1264

1580

<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:

0.00801

AC:

1206

AN:

150552

Hom.:

Cov.:

AF XY:

0.00766

AC XY:

563

AN XY:

73524

show subpopulations

African (AFR)

AF:

0.0144

AC:

589

AN:

40972

American (AMR)

AF:

0.00482

AC:

AN:

15152

Ashkenazi Jewish (ASJ)

AF:

0.00665

AC:

AN:

3460

East Asian (EAS)

AF:

0.00719

AC:

AN:

5006

South Asian (SAS)

AF:

0.00929

AC:

AN:

4734

European-Finnish (FIN)

AF:

0.000863

AC:

AN:

10434

Middle Eastern (MID)

AF:

0.0276

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00585

AC:

395

AN:

67510

Other (OTH)

AF:

0.0110

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

104

155

207

259

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00306

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (4)

CACNA1A-related disorder (1)

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

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.0

Mutation Taster

=74/26

polymorphism

(source)

Splicing

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

Publications

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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