chr8-37738028-A-G

Position:

• chr8-37738028-A-G

Variant summary

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

The NM_007175.8(ERLIN2):​c.106A>G​(p.Arg36Gly) variant causes a missense, splice region change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERLIN2 NM_007175.8 missense, splice_region
• Scores: Splicing: ADA: 0.9962
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.66

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: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERLIN2	NM_007175.8	c.106A>G	p.Arg36Gly	missense_variant, splice_region_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.106A>G	p.Arg36Gly	missense_variant, splice_region_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

Oct 01, 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 sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 36 of the ERLIN2 protein (p.Arg36Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	.;.;D;.;D;.;.;D;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	.;.;.;.;D;.;D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.7	M;M;M;M;M;M;M;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.4	D;D;D;.;D;D;D;D;.
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0050	D;D;D;.;D;D;D;D;.
Sift4G	Uncertain	0.0030	D;D;D;.;D;D;D;D;D
Polyphen		1.0	D;D;D;D;D;D;D;.;D
Vest4		0.85
MutPred		0.73		Loss of methylation at R36 (P = 0.0047);Loss of methylation at R36 (P = 0.0047);Loss of methylation at R36 (P = 0.0047);Loss of methylation at R36 (P = 0.0047);Loss of methylation at R36 (P = 0.0047);Loss of methylation at R36 (P = 0.0047);Loss of methylation at R36 (P = 0.0047);Loss of methylation at R36 (P = 0.0047);Loss of methylation at R36 (P = 0.0047);
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.70
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.36		Position offset: 1

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: chr8-37595546;