dbSNP rs749638821: CACNA1A:p.His2219del (chr19-13208877-GGAT-G) – 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.6656_6658delATC(p.His2219del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00156 in 1,373,696 control chromosomes in the GnomAD database, including 2 homozygotes. 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 0.00063 ( 1 hom., cov: 27)

Exomes 𝑓: 0.0017 ( 1 hom. )

Consequence

CACNA1A
NM_001127222.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

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-GGAT-G is Benign according to our data. Variant chr19-13208877-GGAT-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 377042.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000631 (95/150506) while in subpopulation AMR AF = 0.000858 (13/15154). AF 95% confidence interval is 0.000507. There are 1 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 27. This position passed quality control check.

BS2

High AC in GnomAd4 at 95 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.6656_6658delATC	p.His2219del	disruptive_inframe_deletion	Exon 46 of 47	NP_001120694.1	O00555-8
CACNA1A	NM_001127221.2	MANE Plus Clinical	c.6659_6661delATC	p.His2220del	disruptive_inframe_deletion	Exon 46 of 47	NP_001120693.1	O00555-3
CACNA1A	NM_023035.3		c.6674_6676delATC	p.His2225del	disruptive_inframe_deletion	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.6656_6658delATC	p.His2219del	disruptive_inframe_deletion	Exon 46 of 47	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.6659_6661delATC	p.His2220del	disruptive_inframe_deletion	Exon 46 of 47	ENSP00000489913.1	O00555-3
CACNA1A	ENST00000638029.1	TSL:5	c.6674_6676delATC	p.His2225del	disruptive_inframe_deletion	Exon 47 of 48	ENSP00000489829.1	A0A087WW63

Frequencies

GnomAD3 genomes

AF:

0.000618

AC:

AN:

150402

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000489

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000859

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000598

Gnomad SAS

AF:

0.000844

Gnomad FIN

AF:

0.00115

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000578

Gnomad OTH

AF:

0.000484

GnomAD2 exomes

AF:

0.00226

AC:

265

AN:

117448

AF XY:

0.00219

show subpopulations

Gnomad AFR exome

AF:

0.000904

Gnomad AMR exome

AF:

0.00120

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00127

Gnomad FIN exome

AF:

0.00632

Gnomad NFE exome

AF:

0.00282

Gnomad OTH exome

AF:

0.00247

GnomAD4 exome

AF:

0.00167

AC:

2044

AN:

1223190

Hom.:

AF XY:

0.00169

AC XY:

1023

AN XY:

604492

show subpopulations

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

African (AFR)

AF:

0.00147

AC:

AN:

25936

American (AMR)

AF:

0.00127

AC:

AN:

31568

Ashkenazi Jewish (ASJ)

AF:

0.000835

AC:

AN:

22754

East Asian (EAS)

AF:

0.00107

AC:

AN:

28966

South Asian (SAS)

AF:

0.00141

AC:

102

AN:

72406

European-Finnish (FIN)

AF:

0.00173

AC:

AN:

29482

Middle Eastern (MID)

AF:

0.000590

AC:

AN:

5088

European-Non Finnish (NFE)

AF:

0.00175

AC:

1672

AN:

955878

Other (OTH)

AF:

0.00172

AC:

AN:

51112

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

190

381

571

762

952

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.000631

AC:

AN:

150506

Hom.:

Cov.:

AF XY:

0.000721

AC XY:

AN XY:

73498

show subpopulations

African (AFR)

AF:

0.000537

AC:

AN:

40974

American (AMR)

AF:

0.000858

AC:

AN:

15154

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.000600

AC:

AN:

5004

South Asian (SAS)

AF:

0.000845

AC:

AN:

4734

European-Finnish (FIN)

AF:

0.00115

AC:

AN:

10416

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.000578

AC:

AN:

67486

Other (OTH)

AF:

0.000479

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.0150

Hom.:

Bravo

AF:

0.000586

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

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

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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