chr19-13207858-CCTGCTGCTGCTGCTGCTGCTG-C

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_6975delCAGCAGCAGCAGCAGCAGCAG(p.Gln2319_Gln2325del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000175 in 1,430,526 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: 𝑓 0.00034 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.785

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 afr. GnomAd4 allele frequency = 0.000345 (51/147904) while in subpopulation AFR AF = 0.000871 (35/40206). AF 95% confidence interval is 0.000643. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High AC in GnomAd4 at 51 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.6955_6975delCAGCAGCAGCAGCAGCAGCAG	p.Gln2319_Gln2325del	conservative_inframe_deletion	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_6975delCAGCAGCAGCAGCAGCAGCAG	p.Gln2319_Gln2325del	conservative_inframe_deletion	Exon 47 of 47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 link	c.6973_6993delCAGCAGCAGCAGCAGCAGCAG	p.Gln2325_Gln2331del	conservative_inframe_deletion	Exon 48 of 48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.6961_6981delCAGCAGCAGCAGCAGCAGCAG	p.Gln2321_Gln2327del	conservative_inframe_deletion	Exon 47 of 47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.6958_6978delCAGCAGCAGCAGCAGCAGCAG	p.Gln2320_Gln2326del	conservative_inframe_deletion	Exon 47 of 47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 link	c.6958_6978delCAGCAGCAGCAGCAGCAGCAG	p.Gln2320_Gln2326del	conservative_inframe_deletion	Exon 47 of 47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 link	c.6922_6942delCAGCAGCAGCAGCAGCAGCAG	p.Gln2308_Gln2314del	conservative_inframe_deletion	Exon 46 of 46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 link	c.6817_6837delCAGCAGCAGCAGCAGCAGCAG	p.Gln2273_Gln2279del	conservative_inframe_deletion	Exon 46 of 46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636768.2 link	n.1216_1236delCAGCAGCAGCAGCAGCAGCAG		non_coding_transcript_exon_variant	Exon 45 of 45	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000713789.1 link	n.2134_2154delCAGCAGCAGCAGCAGCAGCAG		non_coding_transcript_exon_variant	Exon 47 of 47			ENSP00000519091.1
CACNA1A	ENST00000636389.1 link	c.41_61delCAGCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 link	c.167_187delCAGCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 48 of 48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000635895.1 link	c.167_187delCAGCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 47 of 47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 link	c.167_187delCAGCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 47 of 47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 link	c.167_187delCAGCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 46 of 46	5		ENSP00000489777.1	O00555-5
CACNA1A	ENST00000636768.2 link	n.1216_1236delCAGCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 45 of 45	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000713789.1 link	n.2134_2154delCAGCAGCAGCAGCAGCAGCAG		3_prime_UTR_variant	Exon 47 of 47			ENSP00000519091.1
CACNA1A	ENST00000636549.1 link	c.167_187delCAGCAGCAGCAGCAGCAGCAG		downstream_gene_variant		5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 link	c.167_187delCAGCAGCAGCAGCAGCAGCAG		downstream_gene_variant		5		ENSP00000489715.1	A0A1B0GTI4

Frequencies

GnomAD3 genomes

AF:

0.000352

AC:

AN:

147802

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000873

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000268

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000402

Gnomad MID

AF:

0.00333

Gnomad NFE

AF:

0.000120

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000156

AC:

200

AN:

1282622

Hom.:

AF XY:

0.000184

AC XY:

116

AN XY:

631208

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000522

AC:

AN:

24918

American (AMR)

AF:

0.000166

AC:

AN:

24092

Ashkenazi Jewish (ASJ)

AF:

0.0000921

AC:

AN:

21710

East Asian (EAS)

AF:

0.000406

AC:

AN:

29580

South Asian (SAS)

AF:

0.000550

AC:

AN:

65408

European-Finnish (FIN)

AF:

0.000570

AC:

AN:

33312

Middle Eastern (MID)

AF:

0.000267

AC:

AN:

3750

European-Non Finnish (NFE)

AF:

0.0000984

AC:

101

AN:

1026754

Other (OTH)

AF:

0.000226

AC:

AN:

53098

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.383

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:

0.000345

AC:

AN:

147904

Hom.:

Cov.:

AF XY:

0.000361

AC XY:

AN XY:

72002

show subpopulations

African (AFR)

AF:

0.000871

AC:

AN:

40206

American (AMR)

AF:

0.000267

AC:

AN:

14968

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3436

East Asian (EAS)

AF:

0.00

AC:

AN:

4816

South Asian (SAS)

AF:

0.00

AC:

AN:

4704

European-Finnish (FIN)

AF:

0.000402

AC:

AN:

9952

Middle Eastern (MID)

AF:

0.00

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.000120

AC:

AN:

66606

Other (OTH)

AF:

0.00

AC:

AN:

2044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.531

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

0.79

Mutation Taster

=194/6

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