rs1553338016

Positions:

• chr1-181732637-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001205293.3(CACNA1E):​c.2551A>G​(p.Ser851Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1E NM_001205293.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.72

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.092066854).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.2551A>G	p.Ser851Gly	missense_variant	20/48	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.2551A>G	p.Ser851Gly	missense_variant	20/48	1	NM_001205293.3	ENSP00000356545	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	.;.;.;T;T;.;T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.75	.;.;T;.;T;T;T;T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.092	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.0	N;.;.;N;.;N;N;.
MutationTaster	Benign	0.56	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.79	N;.;N;N;.;.;.;.
REVEL	Benign	0.27
Sift	Benign	0.60	T;.;T;T;.;.;.;.
Sift4G	Benign	0.39	T;T;T;T;T;T;T;T
Polyphen		0.015	B;B;.;B;.;B;B;B
Vest4		0.074
MutPred		0.21		Loss of phosphorylation at S851 (P = 0.0035);.;.;Loss of phosphorylation at S851 (P = 0.0035);.;Loss of phosphorylation at S851 (P = 0.0035);Loss of phosphorylation at S851 (P = 0.0035);.;
MVP		0.73
MPC		0.51
ClinPred		0.15	T
GERP RS		3.0
Varity_R		0.095
gMVP		0.44

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

LitVar

Other links and lift over

dbSNP: rs1553338016; hg19: chr1-181701773;