8-37740444-C-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP2 PP3 PP5_Very_Strong

The NM_007175.8(ERLIN2):c.187C>A(p.Gln63Lys) variant causes a missense, splice region 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q63P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERLIN2 NM_007175.8 missense, splice_region
• Scores: Splicing: ADA: 0.9686
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.65

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 Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, ERLIN2
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 8-37740444-C-A is Pathogenic according to our data. Variant chr8-37740444-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 859651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERLIN2	NM_007175.8	c.187C>A	p.Gln63Lys	missense_variant, splice_region_variant	3/12	ENST00000519638.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERLIN2	ENST00000519638.3	c.187C>A	p.Gln63Lys	missense_variant, splice_region_variant	3/12	2	NM_007175.8	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 28, 2022

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 63 of the ERLIN2 protein (p.Gln63Lys). This missense change has been observed in individual(s) with clinical features of autosomal dominant hereditary spastic paraplegia (PMID: 32147972; Invitae). In at least one individual the variant was observed to be de novo. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 859651). -

Hereditary spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Paris Brain Institute, Inserm - ICM

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.8	M;M;M;M;M;M;M;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.8	D;D;D;.;D;D;D;D;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0040	D;D;D;.;D;D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;.;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D;.;D
Vest4		0.82
MutPred		0.78		Gain of methylation at Q63 (P = 0.0176);Gain of methylation at Q63 (P = 0.0176);Gain of methylation at Q63 (P = 0.0176);Gain of methylation at Q63 (P = 0.0176);Gain of methylation at Q63 (P = 0.0176);Gain of methylation at Q63 (P = 0.0176);Gain of methylation at Q63 (P = 0.0176);Gain of methylation at Q63 (P = 0.0176);Gain of methylation at Q63 (P = 0.0176);
MVP		0.99
MPC		2.4
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.65
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.84
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: rs1802811311; hg19: chr8-37597962;