rs199512932

Variant names:

• chr19-13286829-G-A
• rs199512932
• NM_001127222.2:c.3227C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_023035.3(CACNA1A):​c.3239C>T​(p.Ala1080Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000412 in 1,613,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. A1080T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: CACNA1A NM_023035.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 1.39
• Publications: 2 publications found

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

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08718267).
• BP6: Variant 19-13286829-G-A is Benign according to our data. Variant chr19-13286829-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 385136.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000243 (37/152126) while in subpopulation NFE AF = 0.000456 (31/68040). AF 95% confidence interval is 0.000329. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 37 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_023035.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1A	NM_001127222.2	MANE Select	c.3227C>T	p.Ala1076Val	missense	Exon 20 of 47	NP_001120694.1
	CACNA1A	NM_001127221.2	MANE Plus Clinical	c.3230C>T	p.Ala1077Val	missense	Exon 20 of 47	NP_001120693.1
	CACNA1A	NM_023035.3		c.3239C>T	p.Ala1080Val	missense	Exon 20 of 48	NP_075461.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1A	ENST00000360228.11	TSL:1 MANE Select	c.3227C>T	p.Ala1076Val	missense	Exon 20 of 47	ENSP00000353362.5
	CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.3230C>T	p.Ala1077Val	missense	Exon 20 of 47	ENSP00000489913.1
	CACNA1A	ENST00000638029.1	TSL:5	c.3239C>T	p.Ala1080Val	missense	Exon 20 of 48	ENSP00000489829.1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152126 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

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: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000191 AC: 47 AN: 245950 AF XY: 0.000216

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: 0.000559

Gnomad NFE exome AF: 0.000306

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000429 AC: 627 AN: 1461452 Hom.: 0 Cov.: 35 AF XY: 0.000424 AC XY: 308 AN XY: 727022

African (AFR) AF: 0.000119 AC: 4 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86234

European-Finnish (FIN) AF: 0.000263 AC: 14 AN: 53318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000525 AC: 584 AN: 1111796

Other (OTH) AF: 0.000414 AC: 25 AN: 60338

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152126 Hom.: 0 Cov.: 31 AF XY: 0.000202 AC XY: 15 AN XY: 74318

African (AFR) AF: 0.0000242 AC: 1 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000387 Hom.: 1

Bravo AF: 0.000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000608 AC: 5

ExAC AF: 0.000149 AC: 18

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	CACNA1A-related disorder (1)
-	1	-	Developmental and epileptic encephalopathy, 42 (1)
-	-	1	Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 (1)
-	-	1	Inborn genetic diseases (1)
-	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	Benign	0.088
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	16
DANN	Benign	0.90
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.62	D
MetaRNN	Benign	0.087	T
MetaSVM	Uncertain	-0.056	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.4
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.20
Sift	Benign	0.18	T
Sift4G	Benign	0.55	T
Vest4		0.24
MVP		0.76
MPC		0.015
ClinPred		0.037	T
GERP RS		3.0
Varity_R		0.026
gMVP		0.49
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs199512932; hg19: chr19-13397643;