rs778291283

Variant names:

• chr1-181720261-A-C
• rs778291283
• NM_001205293.3:c.1807A>C

Your query was ambiguous. Multiple possible variants found:

• chr1-181720261-A-C
• chr1-181720261-A-G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001205293.3(CACNA1E):​c.1807A>C​(p.Ile603Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1E NM_001205293.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.20
• Publications: 3 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: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.756
• PP5: Variant 1-181720261-A-C is Pathogenic according to our data. Variant chr1-181720261-A-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 390468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1E	NM_001205293.3	MANE Select	c.1807A>C	p.Ile603Leu	missense	Exon 14 of 48	NP_001192222.1
	CACNA1E	NM_000721.4		c.1807A>C	p.Ile603Leu	missense	Exon 14 of 47	NP_000712.2
	CACNA1E	NM_001205294.2		c.1807A>C	p.Ile603Leu	missense	Exon 14 of 46	NP_001192223.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1E	ENST00000367573.7	TSL:1 MANE Select	c.1807A>C	p.Ile603Leu	missense	Exon 14 of 48	ENSP00000356545.2
	CACNA1E	ENST00000360108.7	TSL:5	c.1807A>C	p.Ile603Leu	missense	Exon 14 of 47	ENSP00000353222.3
	CACNA1E	ENST00000367570.6	TSL:1	c.1807A>C	p.Ile603Leu	missense	Exon 14 of 47	ENSP00000356542.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Developmental and epileptic encephalopathy, 69 (2)
1	-	-	Developmental and epileptic encephalopathy (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.5	L
PhyloP100		9.2
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.80
Sift	Benign	0.12	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.94	P
Vest4		0.65
MutPred		0.67		Loss of ubiquitination at K601 (P = 0.1231)
MVP		0.87
MPC		1.2
ClinPred		0.95	D
GERP RS		5.2
Varity_R		0.37
gMVP		0.93
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs778291283; hg19: chr1-181689397;