rs376248243

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001127222.2(CACNA1A):c.4388+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000194 in 1,599,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000090 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 splice_region, intron

Scores

Splicing: ADA: 0.00006392

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.489

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP6

Variant 19-13259556-C-T is Benign according to our data. Variant chr19-13259556-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 446926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.4388+8G>A		splice_region_variant, intron_variant	Intron 27 of 46	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2 link	c.4391+8G>A		splice_region_variant, intron_variant	Intron 27 of 46	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
CACNA1A	ENST00000360228.11 link	c.4388+8G>A	splice_region_variant, intron_variant	Intron 27 of 46	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2 link	c.4391+8G>A	splice_region_variant, intron_variant	Intron 27 of 46	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1 link	c.4400+8G>A	splice_region_variant, intron_variant	Intron 27 of 47	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7 link	c.4394+8G>A	splice_region_variant, intron_variant	Intron 27 of 46	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1 link	c.4391+8G>A	splice_region_variant, intron_variant	Intron 27 of 46	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1 link	c.4391+8G>A	splice_region_variant, intron_variant	Intron 27 of 46	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1 link	c.4391+8G>A	splice_region_variant, intron_variant	Intron 27 of 45	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1 link	c.4250+8G>A	splice_region_variant, intron_variant	Intron 26 of 45	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1 link	c.4391+8G>A	splice_region_variant, intron_variant	Intron 27 of 46	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1 link	c.4400+8G>A	splice_region_variant, intron_variant	Intron 27 of 47	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1 link	c.4391+8G>A	splice_region_variant, intron_variant	Intron 27 of 47	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1 link	c.4394+8G>A	splice_region_variant, intron_variant	Intron 27 of 46	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1 link	c.4391+8G>A	splice_region_variant, intron_variant	Intron 27 of 46	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1 link	c.4391+8G>A	splice_region_variant, intron_variant	Intron 27 of 45	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2 link	n.4391+8G>A	splice_region_variant, intron_variant	Intron 27 of 44	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.4388+8G>A	splice_region_variant, intron_variant	Intron 27 of 46			ENSP00000519091.1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

151932

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000411

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.0000176

AC:

AN:

227426

AF XY:

0.0000326

show subpopulations

Gnomad AFR exome

AF:

0.000296

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000898

AC:

AN:

1447074

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

718150

show subpopulations

African (AFR)

AF:

0.000331

AC:

AN:

33242

American (AMR)

AF:

0.00

AC:

AN:

42796

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25716

East Asian (EAS)

AF:

0.00

AC:

AN:

39290

South Asian (SAS)

AF:

0.00

AC:

AN:

83678

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

9.06e-7

AC:

AN:

1104230

Other (OTH)

AF:

0.0000167

AC:

AN:

59816

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.000118

AC:

AN:

151932

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74200

show subpopulations

African (AFR)

AF:

0.000411

AC:

AN:

41328

American (AMR)

AF:

0.00

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67978

Other (OTH)

AF:

0.000479

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.000164

Hom.:

Bravo

AF:

0.000106

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Oct 28, 2016

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42

Benign:1

Dec 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CACNA1A-related disorder

Benign:1

Oct 24, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

3.5

(source)

DANN

Benign

0.74

PhyloP100

0.49

PromoterAI

0.0033

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000064

dbscSNV1_RF

Benign

0.026

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over