1-181794864-G-A

Variant names:

• chr1-181794864-G-A
• rs1553360130
• NM_001205293.3:c.6028G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP6

The NM_001205293.3(CACNA1E):​c.6028G>A​(p.Val2010Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000206 in 1,455,966 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CACNA1E NM_001205293.3 missense, splice_region
• Scores: Splicing: ADA: 0.9776
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.54
• Publications: 0 publications found

Genes affected

CACNA1E (HGNC:1392): (calcium voltage-gated channel subunit alpha1 E) Voltage-dependent calcium channels are multisubunit complexes consisting of alpha-1, alpha-2, beta, and delta subunits in a 1:1:1:1 ratio. These 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, gene expression, cell motility, cell division and cell death. This gene encodes the alpha-1E subunit of the R-type calcium channels, which belong to the 'high-voltage activated' group that maybe involved in the modulation of firing patterns of neurons important for information processing. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Apr 2011]

CACNA1E Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 69

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Illumina
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 1-181794864-G-A is Benign according to our data. Variant chr1-181794864-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 521249.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001205293.3. 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
	CACNA1E	NM_001205293.3	MANE Select	c.6028G>A	p.Val2010Met	missense splice_region	Exon 46 of 48	NP_001192222.1
	CACNA1E	NM_000721.4		c.5899G>A	p.Val1967Met	missense splice_region	Exon 45 of 47	NP_000712.2
	CACNA1E	NM_001205294.2		c.5842G>A	p.Val1948Met	missense splice_region	Exon 44 of 46	NP_001192223.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1E	ENST00000367573.7	TSL:1 MANE Select	c.6028G>A	p.Val2010Met	missense splice_region	Exon 46 of 48	ENSP00000356545.2
	CACNA1E	ENST00000360108.7	TSL:5	c.5971G>A	p.Val1991Met	missense splice_region	Exon 45 of 47	ENSP00000353222.3
	CACNA1E	ENST00000367570.6	TSL:1	c.5899G>A	p.Val1967Met	missense splice_region	Exon 45 of 47	ENSP00000356542.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1455966 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 723990

African (AFR) AF: 0.0000603 AC: 2 AN: 33188

American (AMR) AF: 0.00 AC: 0 AN: 44012

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25946

East Asian (EAS) AF: 0.00 AC: 0 AN: 39486

South Asian (SAS) AF: 0.00 AC: 0 AN: 85366

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108838

Other (OTH) AF: 0.00 AC: 0 AN: 60086

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	1.5	L
PhyloP100		4.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.62	N
REVEL	Uncertain	0.48
Sift	Benign	0.21	T
Sift4G	Benign	0.28	T
Polyphen		0.99	D
Vest4		0.55
MutPred		0.22		Loss of stability (P = 0.065)
MVP		0.85
MPC		0.83
ClinPred		0.63	D
GERP RS		5.9
Varity_R		0.13
gMVP		0.34
Mutation Taster		=61/39	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Benign	0.71
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: rs1553360130; hg19: chr1-181764000;