rs1554515558

Variant names:

• chr8-37738016-G-T
• rs1554515558
• NM_007175.8:c.94G>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_007175.8(ERLIN2):​c.94G>T​(p.Gly32Trp) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERLIN2 NM_007175.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.57

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERLIN2	NM_007175.8	c.94G>T	p.Gly32Trp	missense_variant	Exon 2 of 12	ENST00000519638.3	NP_009106.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERLIN2	ENST00000519638.3	c.94G>T	p.Gly32Trp	missense_variant	Exon 2 of 12	2	NM_007175.8	ENSP00000428112.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia Uncertain:1

May 27, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant has uncertain impact on ERLIN2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces glycine with tryptophan at codon 32 of the ERLIN2 protein (p.Gly32Trp). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a ERLIN2-related disease. 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	.;T;.;D;.;D;.;.;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	.;D;.;.;.;D;.;D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.5	M;.;M;M;M;M;M;M;.;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.0	D;D;D;D;.;D;D;D;D;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D;D;.;D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;.;D;D;D;D;D
Polyphen		1.0	D;.;D;D;D;D;D;D;.;D
Vest4		0.81
MutPred		0.69		Loss of methylation at R36 (P = 0.0355);Loss of methylation at R36 (P = 0.0355);Loss of methylation at R36 (P = 0.0355);Loss of methylation at R36 (P = 0.0355);Loss of methylation at R36 (P = 0.0355);Loss of methylation at R36 (P = 0.0355);Loss of methylation at R36 (P = 0.0355);Loss of methylation at R36 (P = 0.0355);Loss of methylation at R36 (P = 0.0355);Loss of methylation at R36 (P = 0.0355);
MVP		0.97
MPC		2.3
ClinPred		1.0	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.98

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: rs1554515558; hg19: chr8-37595534;