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GeneBe

8-37740393-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2

The NM_007175.8(ERLIN2):c.136G>A(p.Gly46Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000701 in 1,612,698 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000073 ( 1 hom. )

Consequence

ERLIN2
NM_007175.8 missense

Scores

2
8
7

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.50
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 1 ACMG points.

PP2
Missense variant where missense usually causes diseases, ERLIN2

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ERLIN2NM_007175.8 linkuse as main transcriptc.136G>A p.Gly46Ser missense_variant 3/12 ENST00000519638.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ERLIN2ENST00000519638.3 linkuse as main transcriptc.136G>A p.Gly46Ser missense_variant 3/122 NM_007175.8 P1O94905-1

Frequencies

GnomAD3 genomes
AF:
0.0000395
AC:
6
AN:
151876
Hom.:
0
Cov.:
32
show subpopulations
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:
0.000208
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000736
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000557
AC:
14
AN:
251456
Hom.:
1
AF XY:
0.0000662
AC XY:
9
AN XY:
135900
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.000196
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000615
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000732
AC:
107
AN:
1460822
Hom.:
1
Cov.:
30
AF XY:
0.0000674
AC XY:
49
AN XY:
726756
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000505
Gnomad4 SAS exome
AF:
0.000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000801
Gnomad4 OTH exome
AF:
0.0000829
GnomAD4 genome
AF:
0.0000395
AC:
6
AN:
151876
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74194
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000736
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000845
Hom.:
0
Bravo
AF:
0.0000378
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000906
AC:
11
EpiCase
AF:
0.000109
EpiControl
AF:
0.000119

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeAug 31, 2022In 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with ERLIN2-related conditions. This variant is present in population databases (rs372839403, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 46 of the ERLIN2 protein (p.Gly46Ser). -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 11, 2022The c.136G>A (p.G46S) alteration is located in exon 3 (coding exon 2) of the ERLIN2 gene. This alteration results from a G to A substitution at nucleotide position 136, causing the glycine (G) at amino acid position 46 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.097
BayesDel_addAF
Benign
-0.065
T
BayesDel_noAF
Uncertain
-0.060
Cadd
Uncertain
24
Dann
Uncertain
1.0
Eigen
Uncertain
0.36
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Pathogenic
0.97
D
M_CAP
Uncertain
0.19
D
MetaRNN
Uncertain
0.43
T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.64
D
MutationAssessor
Benign
1.5
L;L;L;L;L;L;L;.;L
MutationTaster
Benign
1.0
D;D;D;D;D;D
PrimateAI
Pathogenic
0.83
D
PROVEAN
Benign
-2.0
N;N;N;.;N;N;N;N;.
REVEL
Uncertain
0.51
Sift
Benign
0.27
T;T;T;.;T;T;T;T;.
Sift4G
Benign
0.35
T;T;T;.;T;T;T;T;T
Polyphen
0.17
B;D;P;B;P;D;B;.;D
Vest4
0.46
MVP
0.97
MPC
1.1
ClinPred
0.14
T
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.20
gMVP
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs372839403; hg19: chr8-37597911; COSMIC: COSV99379876; COSMIC: COSV99379876; API