19-13208879-ATGGTGGTGGTGGTGGTGG-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3BP3

The NM_001127222.2(CACNA1A):c.6639_6656delCCACCACCACCACCACCA(p.His2214_His2219del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000766 in 1,305,510 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.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.7e-7 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.26

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.6639_6656delCCACCACCACCACCACCA	p.His2214_His2219del	disruptive_inframe_deletion	Exon 46 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2 link	c.6642_6659delCCACCACCACCACCACCA	p.His2215_His2220del	disruptive_inframe_deletion	Exon 46 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1A	ENST00000360228.11 link	c.6639_6656delCCACCACCACCACCACCA	p.His2214_His2219del	disruptive_inframe_deletion	Exon 46 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2 link	c.6642_6659delCCACCACCACCACCACCA	p.His2215_His2220del	disruptive_inframe_deletion	Exon 46 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1 link	c.6657_6674delCCACCACCACCACCACCA	p.His2220_His2225del	disruptive_inframe_deletion	Exon 47 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7 link	c.6645_6662delCCACCACCACCACCACCA	p.His2216_His2221del	disruptive_inframe_deletion	Exon 46 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1 link	c.6642_6659delCCACCACCACCACCACCA	p.His2215_His2220del	disruptive_inframe_deletion	Exon 46 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1 link	c.6642_6659delCCACCACCACCACCACCA	p.His2215_His2220del	disruptive_inframe_deletion	Exon 46 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1 link	c.6606_6623delCCACCACCACCACCACCA	p.His2203_His2208del	disruptive_inframe_deletion	Exon 45 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1 link	c.6501_6518delCCACCACCACCACCACCA	p.His2168_His2173del	disruptive_inframe_deletion	Exon 45 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1 link	c.6642_6659delCCACCACCACCACCACCA	p.His2215_His2220del	disruptive_inframe_deletion	Exon 46 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1 link	c.6657_6674delCCACCACCACCACCACCA	p.His2220_His2225del	disruptive_inframe_deletion	Exon 47 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1 link	c.6648_6665delCCACCACCACCACCACCA	p.His2217_His2222del	disruptive_inframe_deletion	Exon 47 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1 link	c.6645_6662delCCACCACCACCACCACCA	p.His2216_His2221del	disruptive_inframe_deletion	Exon 46 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1 link	c.6642_6659delCCACCACCACCACCACCA	p.His2215_His2220del	disruptive_inframe_deletion	Exon 46 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1 link	c.6606_6623delCCACCACCACCACCACCA	p.His2203_His2208del	disruptive_inframe_deletion	Exon 45 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2 link	n.905_922delCCACCACCACCACCACCA		non_coding_transcript_exon_variant	Exon 44 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.1818_1835delCCACCACCACCACCACCA		non_coding_transcript_exon_variant	Exon 46 of 47			ENSP00000519091.1
CACNA1A	ENST00000636768.2 link	n.905_922delCCACCACCACCACCACCA		3_prime_UTR_variant	Exon 44 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.1818_1835delCCACCACCACCACCACCA		3_prime_UTR_variant	Exon 46 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.66e-7

AC:

AN:

1305510

Hom.:

AF XY:

0.00000155

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:

0.00

AC:

AN:

23566

East Asian (EAS)

AF:

0.00

AC:

AN:

34222

South Asian (SAS)

AF:

0.00

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:

9.86e-7

AC:

AN:

1014512

Other (OTH)

AF:

0.00

AC:

AN:

54388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

8.3

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over