8-37749586-C-T

Variant names:

• chr8-37749586-C-T
• rs1554517327
• NM_007175.8:c.452C>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3 PP5_Moderate

The NM_007175.8(ERLIN2):​c.452C>T​(p.Ala151Val) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ERLIN2 NM_007175.8 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.58

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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.782
• PP5: Variant 8-37749586-C-T is Pathogenic according to our data. Variant chr8-37749586-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 458243.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERLIN2	NM_007175.8	c.452C>T	p.Ala151Val	missense_variant	Exon 7 of 12	ENST00000519638.3	NP_009106.1
ERLIN2	NM_001362878.2	c.452C>T	p.Ala151Val	missense_variant	Exon 7 of 12		NP_001349807.1
ERLIN2	XM_047421307.1	c.452C>T	p.Ala151Val	missense_variant	Exon 8 of 13		XP_047277263.1
ERLIN2	XM_047421308.1	c.206C>T	p.Ala69Val	missense_variant	Exon 4 of 9		XP_047277264.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERLIN2	ENST00000519638.3	c.452C>T	p.Ala151Val	missense_variant	Exon 7 of 12	2	NM_007175.8	ENSP00000428112.1
ERLIN2	ENST00000521644.5	c.452C>T	p.Ala151Val	missense_variant	Exon 7 of 12	5		ENSP00000429621.1
ERLIN2	ENST00000518526.5	c.323C>T	p.Ala108Val	missense_variant	Exon 5 of 8	3		ENSP00000429229.1
ERLIN2	ENST00000521993.3	n.381C>T		non_coding_transcript_exon_variant	Exon 6 of 7	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia Pathogenic:1

Sep 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 151 of the ERLIN2 protein (p.Ala151Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant hereditary spastic paraplegia (PMID: 32094424; internal data). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 458243). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ERLIN2 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Spastic paraplegia 18a, autosomal dominant Pathogenic:1

Oct 12, 2023

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;D;D;D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.78	D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.5	.;M;M;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.2	D;D;D;D
REVEL	Uncertain	0.59
Sift	Benign	0.063	T;D;D;D
Sift4G	Benign	0.078	T;D;D;D
Polyphen		0.41	.;B;B;.
Vest4		0.41
MutPred		0.59		.;Loss of ubiquitination at K149 (P = 0.1651);Loss of ubiquitination at K149 (P = 0.1651);Loss of ubiquitination at K149 (P = 0.1651);
MVP		0.94
MPC		1.4
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.51
gMVP		0.77

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: rs1554517327; hg19: chr8-37607104;