19-13208879-ATGGTGGTGGTGGTGGTGG-ATGG

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3BP3BS2

The NM_001127222.2(CACNA1A):c.6642_6656delCCACCACCACCACCA(p.His2215_His2219del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000963 in 1,454,150 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H2214H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000092 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.26

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: Likely_benign. The variant received -4 ACMG points.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

BP3

Nonframeshift variant in repetitive region in NM_001127222.2

BS2

High AC in GnomAdExome4 at 12 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.6642_6656delCCACCACCACCACCA	p.His2215_His2219del	disruptive_inframe_deletion	Exon 46 of 47	NP_001120694.1
CACNA1A	NM_001127221.2	MANE Plus Clinical	c.6645_6659delCCACCACCACCACCA	p.His2216_His2220del	disruptive_inframe_deletion	Exon 46 of 47	NP_001120693.1
CACNA1A	NM_023035.3		c.6660_6674delCCACCACCACCACCA	p.His2221_His2225del	disruptive_inframe_deletion	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.6642_6656delCCACCACCACCACCA	p.His2215_His2219del	disruptive_inframe_deletion	Exon 46 of 47	ENSP00000353362.5
CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.6645_6659delCCACCACCACCACCA	p.His2216_His2220del	disruptive_inframe_deletion	Exon 46 of 47	ENSP00000489913.1
CACNA1A	ENST00000638029.1	TSL:5	c.6660_6674delCCACCACCACCACCA	p.His2221_His2225del	disruptive_inframe_deletion	Exon 47 of 48	ENSP00000489829.1

Frequencies

GnomAD3 genomes

AF:

0.0000135

AC:

AN:

148640

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000220

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000150

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000919

AC:

AN:

1305510

Hom.:

AF XY:

0.00000930

AC XY:

AN XY:

645420

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30304

American (AMR)

AF:

0.00

AC:

AN:

34384

Ashkenazi Jewish (ASJ)

AF:

0.0000424

AC:

AN:

23566

East Asian (EAS)

AF:

0.00

AC:

AN:

34222

South Asian (SAS)

AF:

0.0000260

AC:

AN:

76836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32500

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4798

European-Non Finnish (NFE)

AF:

0.00000789

AC:

AN:

1014512

Other (OTH)

AF:

0.0000184

AC:

AN:

54388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000135

AC:

AN:

148640

Hom.:

Cov.:

AF XY:

0.0000276

AC XY:

AN XY:

72384

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40684

American (AMR)

AF:

0.00

AC:

AN:

14984

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3412

East Asian (EAS)

AF:

0.00

AC:

AN:

4922

South Asian (SAS)

AF:

0.000220

AC:

AN:

4536

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10004

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.0000150

AC:

AN:

66860

Other (OTH)

AF:

0.00

AC:

AN:

2056

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

8.3

Mutation Taster

=107/93

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