rs763958615

Variant names:

• chr8-37753994-A-G
• rs763958615
• NM_007175.8:c.899A>G

Your query was ambiguous. Multiple possible variants found:

• chr8-37753994-A-G
• chr8-37753994-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_007175.8(ERLIN2):​c.899A>G​(p.Asp300Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ERLIN2 NM_007175.8 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.52

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERLIN2	NM_007175.8	c.899A>G	p.Asp300Gly	missense_variant	Exon 12 of 12	ENST00000519638.3	NP_009106.1
ERLIN2	NM_001362878.2	c.899A>G	p.Asp300Gly	missense_variant	Exon 12 of 12		NP_001349807.1
ERLIN2	XM_047421307.1	c.899A>G	p.Asp300Gly	missense_variant	Exon 13 of 13		XP_047277263.1
ERLIN2	XM_047421308.1	c.653A>G	p.Asp218Gly	missense_variant	Exon 9 of 9		XP_047277264.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERLIN2	ENST00000519638.3	c.899A>G	p.Asp300Gly	missense_variant	Exon 12 of 12	2	NM_007175.8	ENSP00000428112.1
ERLIN2	ENST00000521644.5	c.899A>G	p.Asp300Gly	missense_variant	Exon 12 of 12	5		ENSP00000429621.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Uncertain:1

Oct 14, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 not expected to disrupt ERLIN2 protein function. 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 aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 300 of the ERLIN2 protein (p.Asp300Gly). This variant disrupts the p.Asp300 amino acid residue in ERLIN2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28832565; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In 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. -

Inborn genetic diseases Uncertain:1

Apr 14, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.899A>G (p.D300G) alteration is located in exon 12 (coding exon 11) of the ERLIN2 gene. This alteration results from a A to G substitution at nucleotide position 899, causing the aspartic acid (D) at amino acid position 300 to be replaced by a glycine (G). 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	0.26
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Benign	0.019	T
MetaRNN	Uncertain	0.44	T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Uncertain	2.6	M;M;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Uncertain	0.32
Sift	Benign	0.047	D;D;D
Sift4G	Uncertain	0.051	T;T;T
Polyphen		0.88	P;P;.
Vest4		0.50
MutPred		0.22		Loss of ubiquitination at K299 (P = 0.033);Loss of ubiquitination at K299 (P = 0.033);Loss of ubiquitination at K299 (P = 0.033);
MVP		0.79
MPC		0.19
ClinPred		0.97	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.57

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: rs763958615; hg19: chr8-37611512;