19-13208877-G-GGGTGGTGGTGGT

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_001127222.2(CACNA1A):c.6658_6659insACCACCACCACC(p.His2216_His2219dup) variant causes a conservative inframe insertion change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_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. P2220P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000076 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CACNA1A
NM_001127222.2 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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: 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: Uncertain_significance. The variant received 2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001127222.2.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.6658_6659insACCACCACCACC	p.His2216_His2219dup	conservative_inframe_insertion	Exon 46 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2 link	c.6661_6662insACCACCACCACC	p.His2217_His2220dup	conservative_inframe_insertion	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.6658_6659insACCACCACCACC	p.His2216_His2219dup	conservative_inframe_insertion	Exon 46 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2 link	c.6661_6662insACCACCACCACC	p.His2217_His2220dup	conservative_inframe_insertion	Exon 46 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1 link	c.6676_6677insACCACCACCACC	p.His2222_His2225dup	conservative_inframe_insertion	Exon 47 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7 link	c.6664_6665insACCACCACCACC	p.His2218_His2221dup	conservative_inframe_insertion	Exon 46 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1 link	c.6661_6662insACCACCACCACC	p.His2217_His2220dup	conservative_inframe_insertion	Exon 46 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1 link	c.6661_6662insACCACCACCACC	p.His2217_His2220dup	conservative_inframe_insertion	Exon 46 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1 link	c.6625_6626insACCACCACCACC	p.His2205_His2208dup	conservative_inframe_insertion	Exon 45 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1 link	c.6520_6521insACCACCACCACC	p.His2170_His2173dup	conservative_inframe_insertion	Exon 45 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1 link	c.6661_6662insACCACCACCACC	p.His2217_His2220dup	conservative_inframe_insertion	Exon 46 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1 link	c.6676_6677insACCACCACCACC	p.His2222_His2225dup	conservative_inframe_insertion	Exon 47 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1 link	c.6667_6668insACCACCACCACC	p.His2219_His2222dup	conservative_inframe_insertion	Exon 47 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1 link	c.6664_6665insACCACCACCACC	p.His2218_His2221dup	conservative_inframe_insertion	Exon 46 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1 link	c.6661_6662insACCACCACCACC	p.His2217_His2220dup	conservative_inframe_insertion	Exon 46 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1 link	c.6625_6626insACCACCACCACC	p.His2205_His2208dup	conservative_inframe_insertion	Exon 45 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2 link	n.924_925insACCACCACCACC		non_coding_transcript_exon_variant	Exon 44 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.1837_1838insACCACCACCACC		non_coding_transcript_exon_variant	Exon 46 of 47			ENSP00000519091.1
CACNA1A	ENST00000636768.2 link	n.924_925insACCACCACCACC		3_prime_UTR_variant	Exon 44 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.1837_1838insACCACCACCACC		3_prime_UTR_variant	Exon 46 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000764

AC:

AN:

1309460

Hom.:

Cov.:

AF XY:

0.00000309

AC XY:

AN XY:

646842

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28996

American (AMR)

AF:

0.00

AC:

AN:

33894

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24028

East Asian (EAS)

AF:

0.00

AC:

AN:

32968

South Asian (SAS)

AF:

0.00

AC:

AN:

76342

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32216

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5258

European-Non Finnish (NFE)

AF:

0.00000881

AC:

AN:

1021002

Other (OTH)

AF:

0.0000183

AC:

AN:

54756

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.0

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