chr8-37737999-T-C

Position:

• chr8-37737999-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_007175.8(ERLIN2):​c.77T>C​(p.Ile26Thr) 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: 7.68

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
• 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, 0.908

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERLIN2	NM_007175.8	c.77T>C	p.Ile26Thr	missense_variant	2/12	ENST00000519638.3	NP_009106.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERLIN2	ENST00000519638.3	c.77T>C	p.Ile26Thr	missense_variant	2/12	2	NM_007175.8	ENSP00000428112	P1

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 26, 2022

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. 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. 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 isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 26 of the ERLIN2 protein (p.Ile26Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	.;T;.;D;.;D;.;.;D;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	.;D;.;.;.;D;.;D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	M;.;M;M;M;M;M;M;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.8	D;D;D;D;.;D;D;D;D;.
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;D;D;D;.;D;D;D;D;.
Sift4G	Uncertain	0.0020	D;D;D;D;.;D;D;D;D;D
Polyphen		0.85	P;.;D;D;P;D;D;P;.;D
Vest4		0.93
MutPred		0.77		Gain of disorder (P = 0.015);Gain of disorder (P = 0.015);Gain of disorder (P = 0.015);Gain of disorder (P = 0.015);Gain of disorder (P = 0.015);Gain of disorder (P = 0.015);Gain of disorder (P = 0.015);Gain of disorder (P = 0.015);Gain of disorder (P = 0.015);Gain of disorder (P = 0.015);
MVP		0.99
MPC		2.4
ClinPred		0.99	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-37595517;