rs758625682

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_001127222.2(CACNA1A):c.6751G>A(p.Glu2251Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000148 in 1,553,364 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E2251G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000047 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 5.57

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:

ENSG00000300728 (HGNC:):

ENSG00000300728 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 19-13208785-C-T is Benign according to our data. Variant chr19-13208785-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 579755.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1A	NM_001127222.2 link	c.6751G>A	p.Glu2251Lys	missense_variant	Exon 46 of 47	ENST00000360228.11	NP_001120694.1
CACNA1A	NM_001127221.2 link	c.6754G>A	p.Glu2252Lys	missense_variant	Exon 46 of 47	ENST00000638009.2	NP_001120693.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1A	ENST00000360228.11 link	c.6751G>A	p.Glu2251Lys	missense_variant	Exon 46 of 47	1	NM_001127222.2	ENSP00000353362.5
CACNA1A	ENST00000638009.2 link	c.6754G>A	p.Glu2252Lys	missense_variant	Exon 46 of 47	1	NM_001127221.2	ENSP00000489913.1
CACNA1A	ENST00000638029.1 link	c.6769G>A	p.Glu2257Lys	missense_variant	Exon 47 of 48	5		ENSP00000489829.1
CACNA1A	ENST00000573710.7 link	c.6757G>A	p.Glu2253Lys	missense_variant	Exon 46 of 47	5		ENSP00000460092.3
CACNA1A	ENST00000635727.1 link	c.6754G>A	p.Glu2252Lys	missense_variant	Exon 46 of 47	5		ENSP00000490001.1
CACNA1A	ENST00000637769.1 link	c.6754G>A	p.Glu2252Lys	missense_variant	Exon 46 of 47	1		ENSP00000489778.1
CACNA1A	ENST00000636012.1 link	c.6718G>A	p.Glu2240Lys	missense_variant	Exon 45 of 46	5		ENSP00000490223.1
CACNA1A	ENST00000637736.1 link	c.6613G>A	p.Glu2205Lys	missense_variant	Exon 45 of 46	5		ENSP00000489861.1
CACNA1A	ENST00000636389.1 link	c.6754G>A	p.Glu2252Lys	missense_variant	Exon 46 of 47	5		ENSP00000489992.1
CACNA1A	ENST00000637432.1 link	c.6769G>A	p.Glu2257Lys	missense_variant	Exon 47 of 48	5		ENSP00000490617.1
CACNA1A	ENST00000636549.1 link	c.6760G>A	p.Glu2254Lys	missense_variant	Exon 47 of 48	5		ENSP00000490578.1
CACNA1A	ENST00000637927.1 link	c.6757G>A	p.Glu2253Lys	missense_variant	Exon 46 of 47	5		ENSP00000489715.1
CACNA1A	ENST00000635895.1 link	c.6754G>A	p.Glu2252Lys	missense_variant	Exon 46 of 47	5		ENSP00000490323.1
CACNA1A	ENST00000637276.1 link	c.6718G>A	p.Glu2240Lys	missense_variant	Exon 45 of 46	5		ENSP00000489777.1
CACNA1A	ENST00000636768.2 link	n.*1017G>A		non_coding_transcript_exon_variant	Exon 44 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.*1930G>A		non_coding_transcript_exon_variant	Exon 46 of 47			ENSP00000519091.1
CACNA1A	ENST00000636768.2 link	n.*1017G>A		3_prime_UTR_variant	Exon 44 of 45	5		ENSP00000490190.2
CACNA1A	ENST00000713789.1 link	n.*1930G>A		3_prime_UTR_variant	Exon 46 of 47			ENSP00000519091.1

Frequencies

GnomAD3 genomes

AF:

0.0000468

AC:

AN:

149708

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000171

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:

0.00

GnomAD2 exomes

AF:

0.0000113

AC:

AN:

176608

AF XY:

0.0000102

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000128

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000114

AC:

AN:

1403656

Hom.:

Cov.:

AF XY:

0.0000129

AC XY:

AN XY:

695710

show subpopulations

African (AFR)

AF:

0.0000620

AC:

AN:

32272

American (AMR)

AF:

0.00

AC:

AN:

39538

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25068

East Asian (EAS)

AF:

0.00

AC:

AN:

37244

South Asian (SAS)

AF:

0.0000243

AC:

AN:

82398

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34928

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4200

European-Non Finnish (NFE)

AF:

0.0000101

AC:

AN:

1090056

Other (OTH)

AF:

0.0000173

AC:

AN:

57952

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

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:

0.0000468

AC:

AN:

149708

Hom.:

Cov.:

AF XY:

0.0000410

AC XY:

AN XY:

73110

show subpopulations

African (AFR)

AF:

0.000171

AC:

AN:

40892

American (AMR)

AF:

0.00

AC:

AN:

15016

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

4764

South Asian (SAS)

AF:

0.00

AC:

AN:

4462

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10292

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67526

Other (OTH)

AF:

0.00

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000264

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Mar 20, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis indicates that this missense variant does not alter protein structure/function -

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

Benign:1

Apr 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.52

BayesDel_addAF

Uncertain

0.080

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.045

.;.;T;.;.;.;.;.;T;.;.;T;.;.;.;T;.;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.97

D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.70

MetaRNN

Uncertain

0.45

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

0.87

MutationAssessor

Pathogenic

2.9

.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.;.

PhyloP100

5.6

PrimateAI

Pathogenic

0.95

PROVEAN

Benign

-2.1

.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

REVEL

Uncertain

0.55

Sift

Benign

0.057

.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

Sift4G

Benign

0.57

T;T;.;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.

Vest4

0.55

MutPred

0.34

.;.;Gain of methylation at E2252 (P = 0.0101);Gain of methylation at E2252 (P = 0.0101);Gain of methylation at E2252 (P = 0.0101);.;.;Gain of methylation at E2252 (P = 0.0101);.;.;.;.;Gain of methylation at E2252 (P = 0.0101);.;.;.;.;.;

MVP

0.91

MPC

0.61

ClinPred

0.75

GERP RS

3.9

Varity_R

0.19

gMVP

0.34

Mutation Taster

=85/15

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

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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