rs1554517327

Positions:

• chr8-37749586-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ERLIN2 NM_007175.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• 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 4 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, 0.782

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERLIN2	ENST00000519638.3	c.452C>T	p.Ala151Val	missense_variant	7/12	2	NM_007175.8	ENSP00000428112	P1
ERLIN2	ENST00000521644.5	c.452C>T	p.Ala151Val	missense_variant	7/12	5		ENSP00000429621
ERLIN2	ENST00000518526.5	c.323C>T	p.Ala108Val	missense_variant	5/8	3		ENSP00000429229
ERLIN2	ENST00000521993.3	n.381C>T		non_coding_transcript_exon_variant	6/7	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia 18a, autosomal dominant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 12, 2023

- -

Spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 30, 2018

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an ERLIN2-related disease. This sequence change replaces alanine with valine at codon 151 of the ERLIN2 protein (p.Ala151Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. -

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;.
MutationTaster	Benign	1.0	D;D
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;