rs1554516498

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_007175.8(ERLIN2):ā€‹c.277A>Gā€‹(p.Asn93Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

ERLIN2
NM_007175.8 missense

Scores

12
6
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.24
Variant links:
Genes affected
ERLIN2 (HGNC:1356): (ER lipid raft associated 2) This gene encodes a member of the SPFH domain-containing family of lipid raft-associated proteins. The encoded protein is localized to lipid rafts of the endoplasmic reticulum and plays a critical role in inositol 1,4,5-trisphosphate (IP3) signaling by mediating ER-associated degradation of activated IP3 receptors. Mutations in this gene are a cause of spastic paraplegia-18 (SPG18). Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Feb 2012]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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), ERLIN2. . Trascript score misZ 3.3024 (greater than threshold 3.09). GenCC has associacion of gene with hereditary spastic paraplegia 18, juvenile primary lateral sclerosis, recessive intellectual disability-motor dysfunction-multiple joint contractures syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.899

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ERLIN2NM_007175.8 linkuse as main transcriptc.277A>G p.Asn93Asp missense_variant 5/12 ENST00000519638.3 NP_009106.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ERLIN2ENST00000519638.3 linkuse as main transcriptc.277A>G p.Asn93Asp missense_variant 5/122 NM_007175.8 ENSP00000428112 P1O94905-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461808
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727208
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 17, 2023In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ERLIN2 protein function. ClinVar contains an entry for this variant (Variation ID: 458242). This variant has not been reported in the literature in individuals affected with ERLIN2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 93 of the ERLIN2 protein (p.Asn93Asp). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.10
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.48
.;T;.;D;.;D;.;.;D;.
Eigen
Pathogenic
0.99
Eigen_PC
Pathogenic
0.94
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.94
.;D;.;.;.;D;.;D;D;D
M_CAP
Pathogenic
0.40
D
MetaRNN
Pathogenic
0.90
D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.8
M;.;M;M;M;M;M;M;.;M
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Pathogenic
0.82
D
PROVEAN
Pathogenic
-4.8
D;D;D;D;.;D;D;D;D;.
REVEL
Pathogenic
0.86
Sift
Uncertain
0.0050
D;D;D;D;.;D;D;D;D;.
Sift4G
Pathogenic
0.0
D;D;D;D;.;D;D;D;D;D
Polyphen
0.99
D;.;D;D;D;D;D;D;.;D
Vest4
0.84
MutPred
0.67
Gain of relative solvent accessibility (P = 0.0215);.;Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);Gain of relative solvent accessibility (P = 0.0215);
MVP
0.99
MPC
1.3
ClinPred
0.99
D
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.71
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554516498; hg19: chr8-37601913; API