19-13207858-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG

Variant names:

Variant summary

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

The NM_001127222.2(CACNA1A):c.6955_6975dupCAGCAGCAGCAGCAGCAGCAG(p.Gln2319_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 0.000068 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000045 ( 1 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. GnomAd4 allele frequency = 0.0000677 (10/147802) while in subpopulation EAS AF = 0.00103 (5/4832). AF 95% confidence interval is 0.000408. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.6955_6975dupCAGCAGCAGCAGCAGCAGCAG	p.Gln2319_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.6955_6975dupCAGCAGCAGCAGCAGCAGCAG	p.Gln2319_Gln2325dup	conservative_inframe_insertion	Exon 47 of 47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 link	c.6973_6993dupCAGCAGCAGCAGCAGCAGCAG	p.Gln2325_Gln2331dup	conservative_inframe_insertion	Exon 48 of 48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.6961_6981dupCAGCAGCAGCAGCAGCAGCAG	p.Gln2321_Gln2327dup	conservative_inframe_insertion	Exon 47 of 47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.6958_6978dupCAGCAGCAGCAGCAGCAGCAG	p.Gln2320_Gln2326dup	conservative_inframe_insertion	Exon 47 of 47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 link	c.6958_6978dupCAGCAGCAGCAGCAGCAGCAG	p.Gln2320_Gln2326dup	conservative_inframe_insertion	Exon 47 of 47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 link	c.6922_6942dupCAGCAGCAGCAGCAGCAGCAG	p.Gln2308_Gln2314dup	conservative_inframe_insertion	Exon 46 of 46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 link	c.6817_6837dupCAGCAGCAGCAGCAGCAGCAG	p.Gln2273_Gln2279dup	conservative_inframe_insertion	Exon 46 of 46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636768.2 link	n.1216_1236dupCAGCAGCAGCAGCAGCAGCAG		non_coding_transcript_exon_variant	Exon 45 of 45	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000713789.1 link	n.2134_2154dupCAGCAGCAGCAGCAGCAGCAG		non_coding_transcript_exon_variant	Exon 47 of 47			ENSP00000519091.1
CACNA1A	ENST00000636389.1 link	c.41_61dupCAGCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 link	c.167_187dupCAGCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 48 of 48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000635895.1 link	c.167_187dupCAGCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 link	c.167_187dupCAGCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 47 of 47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 link	c.167_187dupCAGCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 46 of 46	5		ENSP00000489777.1	O00555-5
CACNA1A	ENST00000636768.2 link	n.1216_1236dupCAGCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 45 of 45	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000713789.1 link	n.2134_2154dupCAGCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 47 of 47			ENSP00000519091.1
CACNA1A	ENST00000636549.1 link	c.167_187dupCAGCAGCAGCAGCAGCAGCAG		downstream_gene_variant		5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 link	c.167_187dupCAGCAGCAGCAGCAGCAGCAG		downstream_gene_variant		5		ENSP00000489715.1	A0A1B0GTI4

Frequencies

GnomAD3 genomes

AF:

0.0000677

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:

0.00103

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000751

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000452

AC:

AN:

1283938

Hom.:

Cov.:

AF XY:

0.0000475

AC XY:

AN XY:

631946

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24930

American (AMR)

AF:

0.0000415

AC:

AN:

24096

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21718

East Asian (EAS)

AF:

0.000811

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:

0.0000263

AC:

AN:

1027676

Other (OTH)

AF:

0.0000564

AC:

AN:

53146

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000677

AC:

AN:

147802

Hom.:

Cov.:

AF XY:

0.0000417

AC XY:

AN XY:

71886

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40090

American (AMR)

AF:

0.00

AC:

AN:

14948

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3436

East Asian (EAS)

AF:

0.00103

AC:

AN:

4832

South Asian (SAS)

AF:

0.00

AC:

AN:

4710

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9952

Middle Eastern (MID)

AF:

0.00

AC:

AN:

300

European-Non Finnish (NFE)

AF:

0.0000751

AC:

AN:

66616

Other (OTH)

AF:

0.00

AC:

AN:

2022

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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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19-13207858-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG-CCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTG

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