1-181483800-C-G

Position:

• chr1-181483800-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001205293.3(CACNA1E):​c.56C>G​(p.Ser19Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,052 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S19L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CACNA1E NM_001205293.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.94

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1E. . Gene score misZ 5.8125 (greater than the threshold 3.09). Trascript score misZ 6.7013 (greater than threshold 3.09). GenCC has associacion of gene with developmental and epileptic encephalopathy, developmental and epileptic encephalopathy, 69.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.56C>G	p.Ser19Trp	missense_variant	1/48	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.56C>G	p.Ser19Trp	missense_variant	1/48	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.56C>G	p.Ser19Trp	missense_variant	1/47	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.56C>G	p.Ser19Trp	missense_variant	1/47	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.56C>G	p.Ser19Trp	missense_variant	1/46	1		ENSP00000481619.1
CACNA1E	ENST00000524607.6	c.491C>G	p.Ser164Trp	missense_variant	3/12	5		ENSP00000432038.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461052 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726818

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 05, 2020

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	.;.;.;.;D;T;.;D;.
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;.;.;D;.;D;D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Uncertain	0.59	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	.;L;L;.;L;.;L;L;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.2	.;D;.;D;D;D;.;.;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0010	.;D;.;D;D;D;.;.;D
Sift4G	Uncertain	0.014	.;D;D;D;D;D;D;D;D
Polyphen		0.99	.;D;.;.;.;.;D;.;.
Vest4		0.52, 0.51, 0.58, 0.59, 0.56, 0.59, 0.53, 0.56
MutPred		0.20		.;Loss of phosphorylation at S19 (P = 0.0367);Loss of phosphorylation at S19 (P = 0.0367);Loss of phosphorylation at S19 (P = 0.0367);Loss of phosphorylation at S19 (P = 0.0367);Loss of phosphorylation at S19 (P = 0.0367);Loss of phosphorylation at S19 (P = 0.0367);Loss of phosphorylation at S19 (P = 0.0367);Loss of phosphorylation at S19 (P = 0.0367);
MVP		0.83
MPC		2.4
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.55
gMVP		0.53

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-181452936;