rs1361083258

Variant names:

• chr1-181721870-G-A
• rs1361083258
• NM_001205293.3:c.2069G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-181721870-G-A
• chr1-181721870-G-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_001205293.3(CACNA1E):​c.2069G>A​(p.Gly690Asp) 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. 12/21 in silico tools predict a damaging outcome for this variant. 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. G690V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1E NM_001205293.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 8.02

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a transmembrane_region Helical; Name=S6 of repeat II (size 24) in uniprot entity CAC1E_HUMAN there are 20 pathogenic changes around while only 1 benign (95%) in NM_001205293.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-181721870-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1346057.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1E	NM_001205293.3	c.2069G>A	p.Gly690Asp	missense_variant	Exon 16 of 48	ENST00000367573.7	NP_001192222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1E	ENST00000367573.7	c.2069G>A	p.Gly690Asp	missense_variant	Exon 16 of 48	1	NM_001205293.3	ENSP00000356545.2
CACNA1E	ENST00000360108.7	c.2069G>A	p.Gly690Asp	missense_variant	Exon 16 of 47	5		ENSP00000353222.3
CACNA1E	ENST00000367570.6	c.2069G>A	p.Gly690Asp	missense_variant	Exon 16 of 47	1		ENSP00000356542.1
CACNA1E	ENST00000621791.4	c.2069G>A	p.Gly690Asp	missense_variant	Exon 16 of 46	1		ENSP00000481619.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Early infantile epileptic encephalopathy with suppression bursts Pathogenic:1

Nov 01, 2018

Yale Center for Mendelian Genomics, Yale University

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases Uncertain:1

Dec 05, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;D;D;.;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;.;D;.;D;D;D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.6	H;H;.;H;.;H;H;H
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-6.1	D;.;D;D;.;.;.;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0050	D;.;D;D;.;.;.;.
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;.;.;D;.;D
Vest4		0.85
MutPred		0.88		Loss of catalytic residue at G690 (P = 0.3027);Loss of catalytic residue at G690 (P = 0.3027);Loss of catalytic residue at G690 (P = 0.3027);Loss of catalytic residue at G690 (P = 0.3027);Loss of catalytic residue at G690 (P = 0.3027);Loss of catalytic residue at G690 (P = 0.3027);Loss of catalytic residue at G690 (P = 0.3027);Loss of catalytic residue at G690 (P = 0.3027);
MVP		0.99
MPC		1.3
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.79
gMVP		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs1361083258; hg19: chr1-181691006; COSMIC: COSV100701379;