dbSNP rs375354077: CACNA1A:p.Arg2169Cys (chr19-13209333-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_001127222.2(CACNA1A):c.6505C>T(p.Arg2169Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000402 in 1,393,218 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. R2169H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

CACNA1A
NM_001127222.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 3.11

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, Genomics England PanelApp
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet
developmental and epileptic encephalopathy, 42
Inheritance: AD Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
migraine, familial hemiplegic, 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
spinocerebellar ataxia type 6
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
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 -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.087599635).

BP6

Variant 19-13209333-G-A is Benign according to our data. Variant chr19-13209333-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 421988.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000158 (24/152164) while in subpopulation AFR AF = 0.000483 (20/41444). AF 95% confidence interval is 0.00032. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 24 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127222.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNA1A	NM_001127222.2	MANE Select	c.6505C>T	p.Arg2169Cys	missense	Exon 45 of 47	NP_001120694.1
CACNA1A	NM_001127221.2	MANE Plus Clinical	c.6508C>T	p.Arg2170Cys	missense	Exon 45 of 47	NP_001120693.1
CACNA1A	NM_023035.3		c.6523C>T	p.Arg2175Cys	missense	Exon 46 of 48	NP_075461.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CACNA1A	ENST00000360228.11	TSL:1 MANE Select	c.6505C>T	p.Arg2169Cys	missense	Exon 45 of 47	ENSP00000353362.5
CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.6508C>T	p.Arg2170Cys	missense	Exon 45 of 47	ENSP00000489913.1
CACNA1A	ENST00000638029.1	TSL:5	c.6523C>T	p.Arg2175Cys	missense	Exon 46 of 48	ENSP00000489829.1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000109

AC:

AN:

46082

AF XY:

0.0000874

show subpopulations

Gnomad AFR exome

AF:

0.00130

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:

0.0000258

AC:

AN:

1241054

Hom.:

Cov.:

AF XY:

0.0000284

AC XY:

AN XY:

598428

show subpopulations

African (AFR)

AF:

0.000769

AC:

AN:

26012

American (AMR)

AF:

0.0000681

AC:

AN:

14678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17336

East Asian (EAS)

AF:

0.00

AC:

AN:

31010

South Asian (SAS)

AF:

0.00

AC:

AN:

53246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41998

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4596

European-Non Finnish (NFE)

AF:

0.00000799

AC:

AN:

1001404

Other (OTH)

AF:

0.0000591

AC:

AN:

50774

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

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:

0.000158

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.000483

AC:

AN:

41444

American (AMR)

AF:

0.000131

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

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:

0.0000639

Hom.:

Bravo

AF:

0.000196

ESP6500AA

AF:

0.000529

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000582

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

CACNA1A-related disorder (1)

Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 (1)

Inborn genetic diseases (1)

Spinocerebellar ataxia type 6;C1720416:Episodic ataxia type 2;C1832884:Migraine, familial hemiplegic, 1;C4310716:Developmental and epileptic encephalopathy, 42 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.079

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.97

M_CAP

Pathogenic

0.73

MetaRNN

Benign

0.088

MetaSVM

Uncertain

0.63

MutationAssessor

Uncertain

2.7

PhyloP100

3.1

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-4.8

REVEL

Uncertain

0.63

Sift

Uncertain

0.012

Sift4G

Benign

0.13

Vest4

0.66

MVP

0.92

MPC

0.97

ClinPred

0.24

GERP RS

3.5

Varity_R

0.20

gMVP

0.28

Mutation Taster

=79/21

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over