rs559862641

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001127222.2(CACNA1A):c.2844C>G(p.Arg948Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000565 in 1,542,004 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00045 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00058 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.419

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 19-13298789-G-C is Benign according to our data. Variant chr19-13298789-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 386004.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.419 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000447 (68/152258) while in subpopulation SAS AF = 0.00248 (12/4832). AF 95% confidence interval is 0.00143. There are 1 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 68 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.2844C>G	p.Arg948Arg	synonymous_variant	Exon 19 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.2844C>G	p.Arg948Arg	synonymous_variant	Exon 19 of 47	1	NM_001127222.2	ENSP00000353362.5	O00555-8
CACNA1A	ENST00000638029.1 link	c.2856C>G	p.Arg952Arg	synonymous_variant	Exon 19 of 48	5		ENSP00000489829.1	A0A087WW63
CACNA1A	ENST00000573710.7 link	c.2850C>G	p.Arg950Arg	synonymous_variant	Exon 19 of 47	5		ENSP00000460092.3	A0A1C7CYY9
CACNA1A	ENST00000635727.1 link	c.2847C>G	p.Arg949Arg	synonymous_variant	Exon 19 of 47	5		ENSP00000490001.1	A0A1B0GU81
CACNA1A	ENST00000637769.1 link	c.2847C>G	p.Arg949Arg	synonymous_variant	Exon 19 of 47	1		ENSP00000489778.1	A0A1B0GTN7
CACNA1A	ENST00000636012.1 link	c.2847C>G	p.Arg949Arg	synonymous_variant	Exon 19 of 46	5		ENSP00000490223.1	A0A1B0GUS3
CACNA1A	ENST00000637736.1 link	c.2706C>G	p.Arg902Arg	synonymous_variant	Exon 18 of 46	5		ENSP00000489861.1	A0A1B0GTW2
CACNA1A	ENST00000636389.1 link	c.2847C>G	p.Arg949Arg	synonymous_variant	Exon 19 of 47	5		ENSP00000489992.1	A0A1B0GU74
CACNA1A	ENST00000637432.1 link	c.2856C>G	p.Arg952Arg	synonymous_variant	Exon 19 of 48	5		ENSP00000490617.1	O00555-2
CACNA1A	ENST00000636549.1 link	c.2847C>G	p.Arg949Arg	synonymous_variant	Exon 19 of 48	5		ENSP00000490578.1	B5TYJ1
CACNA1A	ENST00000637927.1 link	c.2850C>G	p.Arg950Arg	synonymous_variant	Exon 19 of 47	5		ENSP00000489715.1	A0A1B0GTI4
CACNA1A	ENST00000635895.1 link	c.2847C>G	p.Arg949Arg	synonymous_variant	Exon 19 of 47	5		ENSP00000490323.1	A0A384DVW2
CACNA1A	ENST00000638009.2 link	c.2847C>G	p.Arg949Arg	synonymous_variant	Exon 19 of 47	1		ENSP00000489913.1	O00555-3
CACNA1A	ENST00000637276.1 link	c.2847C>G	p.Arg949Arg	synonymous_variant	Exon 19 of 46	5		ENSP00000489777.1	O00555-5
CACNA1A	ENST00000636768.2 link	n.2847C>G		non_coding_transcript_exon_variant	Exon 19 of 45	5		ENSP00000490190.2	A0A1B0GUP3
CACNA1A	ENST00000713789.1 link	n.2844C>G		non_coding_transcript_exon_variant	Exon 19 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

AF:

0.000447

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000573

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000752

AC:

112

AN:

148926

AF XY:

0.000944

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000689

Gnomad OTH exome

AF:

0.00100

GnomAD4 exome

AF:

0.000578

AC:

803

AN:

1389746

Hom.:

Cov.:

AF XY:

0.000667

AC XY:

459

AN XY:

688140

show subpopulations

African (AFR)

AF:

0.0000684

AC:

AN:

29254

American (AMR)

AF:

0.000564

AC:

AN:

37242

Ashkenazi Jewish (ASJ)

AF:

0.0000407

AC:

AN:

24556

East Asian (EAS)

AF:

0.00

AC:

AN:

34568

South Asian (SAS)

AF:

0.00241

AC:

190

AN:

78944

European-Finnish (FIN)

AF:

0.0000279

AC:

AN:

35878

Middle Eastern (MID)

AF:

0.00598

AC:

AN:

4516

European-Non Finnish (NFE)

AF:

0.000474

AC:

515

AN:

1086980

Other (OTH)

AF:

0.000796

AC:

AN:

57808

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

103

155

206

258

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000447

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41576

American (AMR)

AF:

0.000915

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00248

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000573

AC:

AN:

68004

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000535

Hom.:

Bravo

AF:

0.000359

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CACNA1A: BP4, BP7 -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 25, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jun 30, 2017

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

5.6

(source)

DANN

Benign

0.55

PhyloP100

-0.42

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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