NM_001127222.2:c.3040G>A

Variant names:

• chr19-13298593-C-T
• rs16024
• NM_001127222.2:c.3040G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001127222.2(CACNA1A):​c.3040G>A​(p.Glu1014Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00525 in 1,541,592 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 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. E1014D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (28 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:11
• Conservation: PhyloP100: 3.49
• Publications: 19 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0114197135).
• BP6: Variant 19-13298593-C-T is Benign according to our data. Variant chr19-13298593-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194928.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00376 (573/152266) while in subpopulation NFE AF = 0.00578 (393/68014). AF 95% confidence interval is 0.00531. There are 0 homozygotes in GnomAd4. There are 266 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 573 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1A	NM_001127222.2	MANE Select	c.3040G>A	p.Glu1014Lys	missense	Exon 19 of 47	NP_001120694.1
	CACNA1A	NM_001127221.2	MANE Plus Clinical	c.3043G>A	p.Glu1015Lys	missense	Exon 19 of 47	NP_001120693.1
	CACNA1A	NM_023035.3		c.3052G>A	p.Glu1018Lys	missense	Exon 19 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.3040G>A	p.Glu1014Lys	missense	Exon 19 of 47	ENSP00000353362.5
	CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.3043G>A	p.Glu1015Lys	missense	Exon 19 of 47	ENSP00000489913.1
	CACNA1A	ENST00000638029.1	TSL:5	c.3052G>A	p.Glu1018Lys	missense	Exon 19 of 48	ENSP00000489829.1

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 573 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000472

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00578

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00356 AC: 514 AN: 144488 AF XY: 0.00375

Gnomad AFR exome AF: 0.000671

Gnomad AMR exome AF: 0.00436

Gnomad ASJ exome AF: 0.00232

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000772

Gnomad NFE exome AF: 0.00605

Gnomad OTH exome AF: 0.00545

GnomAD4 exome AF: 0.00541 AC: 7523 AN: 1389326 Hom.: 28 Cov.: 32 AF XY: 0.00532 AC XY: 3645 AN XY: 685244

African (AFR) AF: 0.00107 AC: 32 AN: 29836

American (AMR) AF: 0.00479 AC: 168 AN: 35084

Ashkenazi Jewish (ASJ) AF: 0.00221 AC: 55 AN: 24836

East Asian (EAS) AF: 0.0000294 AC: 1 AN: 33996

South Asian (SAS) AF: 0.00109 AC: 86 AN: 78860

European-Finnish (FIN) AF: 0.00102 AC: 50 AN: 49204

Middle Eastern (MID) AF: 0.00194 AC: 11 AN: 5658

European-Non Finnish (NFE) AF: 0.00633 AC: 6803 AN: 1074306

Other (OTH) AF: 0.00551 AC: 317 AN: 57546

GnomAD4 genome AF: 0.00376 AC: 573 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.00357 AC XY: 266 AN XY: 74470

African (AFR) AF: 0.00147 AC: 61 AN: 41570

American (AMR) AF: 0.00562 AC: 86 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.000472 AC: 5 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00578 AC: 393 AN: 68014

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00496 Hom.: 7

Bravo AF: 0.00427

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00570 AC: 35

ExAC AF: 0.00200 AC: 62

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	4	not provided (7)
-	-	3	not specified (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	-	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Benign	0.88
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.5
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.25
Sift	Benign	0.41	T
Sift4G	Benign	0.33	T
Vest4		0.18
MVP		0.78
MPC		1.2
ClinPred		0.016	T
GERP RS		3.5
Varity_R		0.15
gMVP		0.34
Mutation Taster		=96/4	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: rs16024; hg19: chr19-13409407;