rs561858384

Variant names:

• chr19-13317306-C-T
• rs561858384
• NM_001127222.2:c.1361G>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_001127222.2(CACNA1A):​c.1361G>A​(p.Arg454Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000091 in 1,605,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R454R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000097 (0 hom.)
• Consequence: CACNA1A NM_001127222.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:7 B:1
• Conservation: PhyloP100: 4.13
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, Orphanet
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• spinocerebellar ataxia type 6

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• 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

ENSG00000306107 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.768
• BS2: High AC in GnomAd4 at 5 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1A	NM_001127222.2	MANE Select	c.1361G>A	p.Arg454Gln	missense	Exon 11 of 47	NP_001120694.1	O00555-8
	CACNA1A	NM_001127221.2	MANE Plus Clinical	c.1364G>A	p.Arg455Gln	missense	Exon 11 of 47	NP_001120693.1	O00555-3
	CACNA1A	NM_023035.3		c.1364G>A	p.Arg455Gln	missense	Exon 11 of 48	NP_075461.2	A0A087WW63

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1A	ENST00000360228.11	TSL:1 MANE Select	c.1361G>A	p.Arg454Gln	missense	Exon 11 of 47	ENSP00000353362.5	O00555-8
	CACNA1A	ENST00000638009.2	TSL:1 MANE Plus Clinical	c.1364G>A	p.Arg455Gln	missense	Exon 11 of 47	ENSP00000489913.1	O00555-3
	CACNA1A	ENST00000638029.1	TSL:5	c.1364G>A	p.Arg455Gln	missense	Exon 11 of 48	ENSP00000489829.1	A0A087WW63

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000322 AC: 8 AN: 248320 AF XY: 0.0000445

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: 0.0000710

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000971 AC: 141 AN: 1452792 Hom.: 0 Cov.: 31 AF XY: 0.000111 AC XY: 80 AN XY: 720572

African (AFR) AF: 0.0000600 AC: 2 AN: 33346

American (AMR) AF: 0.00 AC: 0 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.0000507 AC: 2 AN: 39434

South Asian (SAS) AF: 0.00 AC: 0 AN: 86006

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5692

European-Non Finnish (NFE) AF: 0.000117 AC: 129 AN: 1104452

Other (OTH) AF: 0.000117 AC: 7 AN: 59954

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74396

African (AFR) AF: 0.00 AC: 0 AN: 41542

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000773 Hom.: 0

Bravo AF: 0.0000869

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000248 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	3	-	not specified (3)
-	-	1	Episodic ataxia type 2;C4310716:Developmental and epileptic encephalopathy, 42 (1)
-	1	-	Inborn genetic diseases (1)
1	-	-	Tip-toe gait (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.086	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.024	D
Vest4		0.54
MVP		0.91
MPC		2.2
ClinPred		0.78	D
GERP RS		5.8
Varity_R		0.41
gMVP		0.73
Mutation Taster		=9/91	disease causing (ClinVar)

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: rs561858384; hg19: chr19-13428120; COSMIC: COSV64204135; COSMIC: COSV64204135;