1-181483797-A-T

Variant names:

• chr1-181483797-A-T
• rs1379505181
• NM_001205293.3:c.53A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001205293.3(CACNA1E):​c.53A>T​(p.Asp18Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000662 in 150,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D18G) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: CACNA1E NM_001205293.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.18
• 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.39970016).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.53A>T	p.Asp18Val	missense_variant	Exon 1 of 48	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.53A>T	p.Asp18Val	missense_variant	Exon 1 of 48	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.53A>T	p.Asp18Val	missense_variant	Exon 1 of 47	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.53A>T	p.Asp18Val	missense_variant	Exon 1 of 47	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.53A>T	p.Asp18Val	missense_variant	Exon 1 of 46	1		ENSP00000481619.1
CACNA1E	ENST00000524607.6	c.488A>T	p.Asp163Val	missense_variant	Exon 3 of 12	5		ENSP00000432038.2

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 150976 Hom.: 0 Cov.: 31

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: 0.0000961

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000662 AC: 1 AN: 150976 Hom.: 0 Cov.: 31 AF XY: 0.0000136 AC XY: 1 AN XY: 73636

African (AFR) AF: 0.00 AC: 0 AN: 40998

American (AMR) AF: 0.00 AC: 0 AN: 15178

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5064

South Asian (SAS) AF: 0.00 AC: 0 AN: 4756

European-Finnish (FIN) AF: 0.0000961 AC: 1 AN: 10410

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67812

Other (OTH) AF: 0.00 AC: 0 AN: 2062

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	.;.;.;.;T;T;.;T;.
Eigen	Benign	-0.029
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.95	D;.;.;D;.;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.40	T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.074	D
MutationAssessor	Benign	1.0	.;L;L;.;L;.;L;L;L
PhyloP100		2.2
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.4	.;N;.;D;N;.;.;.;.
REVEL	Uncertain	0.50
Sift	Benign	0.040	.;D;.;D;D;.;.;.;.
Sift4G	Benign	0.18	.;T;T;T;T;T;T;T;T
Polyphen		0.16	.;B;.;.;.;.;B;.;.
Vest4		0.22, 0.22, 0.35, 0.41, 0.36, 0.41, 0.36, 0.43
MutPred		0.19		.;Gain of MoRF binding (P = 0.0547);Gain of MoRF binding (P = 0.0547);Gain of MoRF binding (P = 0.0547);Gain of MoRF binding (P = 0.0547);Gain of MoRF binding (P = 0.0547);Gain of MoRF binding (P = 0.0547);Gain of MoRF binding (P = 0.0547);Gain of MoRF binding (P = 0.0547);
MVP		0.92
MPC		2.4
ClinPred		0.83	D
GERP RS		5.3
PromoterAI		-0.021	Neutral
Varity_R		0.14
gMVP		0.59
Mutation Taster		=265/35	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: rs1379505181; hg19: chr1-181452933;