19-13207858-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1BS2

The NM_001127222.2(CACNA1A):c.6958_6975dupCAGCAGCAGCAGCAGCAG(p.Gln2320_Gln2325dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. 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.

Frequency

Genomes: 𝑓 0.000041 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000072 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.00

Publications

10 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: Benign. The variant received -8 ACMG points.

BS1

Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000724 (93/1283932) while in subpopulation EAS AF = 0.00152 (45/29594). AF 95% confidence interval is 0.00117. There are 0 homozygotes in GnomAdExome4. There are 47 alleles in the male GnomAdExome4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.6958_6975dupCAGCAGCAGCAGCAGCAG	p.Gln2320_Gln2325dup	conservative_inframe_insertion	Exon 47 of 47	ENST00000360228.11	NP_001120694.1	O00555-8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1A	ENST00000360228.11 link	c.6958_6975dupCAGCAGCAGCAGCAGCAG	p.Gln2320_Gln2325dup	conservative_inframe_insertion	Exon 47 of 47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 link	c.6976_6993dupCAGCAGCAGCAGCAGCAG	p.Gln2326_Gln2331dup	conservative_inframe_insertion	Exon 48 of 48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.6964_6981dupCAGCAGCAGCAGCAGCAG	p.Gln2322_Gln2327dup	conservative_inframe_insertion	Exon 47 of 47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.6961_6978dupCAGCAGCAGCAGCAGCAG	p.Gln2321_Gln2326dup	conservative_inframe_insertion	Exon 47 of 47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 link	c.6961_6978dupCAGCAGCAGCAGCAGCAG	p.Gln2321_Gln2326dup	conservative_inframe_insertion	Exon 47 of 47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 link	c.6925_6942dupCAGCAGCAGCAGCAGCAG	p.Gln2309_Gln2314dup	conservative_inframe_insertion	Exon 46 of 46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 link	c.6820_6837dupCAGCAGCAGCAGCAGCAG	p.Gln2274_Gln2279dup	conservative_inframe_insertion	Exon 46 of 46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636768.2 link	n.1219_1236dupCAGCAGCAGCAGCAGCAG		non_coding_transcript_exon_variant	Exon 45 of 45	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000713789.1 link	n.2137_2154dupCAGCAGCAGCAGCAGCAG		non_coding_transcript_exon_variant	Exon 47 of 47			ENSP00000519091.1
CACNA1A	ENST00000636389.1 link	c.44_61dupCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 link	c.170_187dupCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 48 of 48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000635895.1 link	c.170_187dupCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 link	c.170_187dupCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 47 of 47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 link	c.170_187dupCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 46 of 46	5		ENSP00000489777.1	O00555-5
CACNA1A	ENST00000636768.2 link	n.1219_1236dupCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 45 of 45	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000713789.1 link	n.2137_2154dupCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 47 of 47			ENSP00000519091.1
CACNA1A	ENST00000636549.1 link	c.170_187dupCAGCAGCAGCAGCAGCAG		downstream_gene_variant		5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 link	c.170_187dupCAGCAGCAGCAGCAGCAG		downstream_gene_variant		5		ENSP00000489715.1	A0A1B0GTI4

Frequencies

GnomAD3 genomes

AF:

0.0000406

AC:

AN:

147802

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:

0.000828

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000300

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000724

AC:

AN:

1283932

Hom.:

Cov.:

AF XY:

0.0000744

AC XY:

AN XY:

631940

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24930

American (AMR)

AF:

0.000125

AC:

AN:

24096

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

21718

East Asian (EAS)

AF:

0.00152

AC:

AN:

29594

South Asian (SAS)

AF:

0.0000457

AC:

AN:

65608

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3752

European-Non Finnish (NFE)

AF:

0.0000321

AC:

AN:

1027670

Other (OTH)

AF:

0.0000753

AC:

AN:

53146

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

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:

0.0000406

AC:

AN:

147904

Hom.:

Cov.:

AF XY:

0.0000556

AC XY:

AN XY:

72002

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40206

American (AMR)

AF:

0.00

AC:

AN:

14968

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3436

East Asian (EAS)

AF:

0.000831

AC:

AN:

4816

South Asian (SAS)

AF:

0.00

AC:

AN:

4704

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9952

Middle Eastern (MID)

AF:

0.00

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.0000300

AC:

AN:

66606

Other (OTH)

AF:

0.00

AC:

AN:

2044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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.:

195

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.0

Mutation Taster

=81/19

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over