8-37744678-G-C

Variant names:

• chr8-37744678-G-C
• rs1338086200
• NM_007175.8:c.406G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_007175.8(ERLIN2):​c.406G>C​(p.Val136Leu) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V136I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERLIN2 NM_007175.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 10.0
• Publications: 0 publications found

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]

ERLIN2 Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 18

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• juvenile primary lateral sclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• recessive intellectual disability-motor dysfunction-multiple joint contractures syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000183154 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_007175.8
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 9 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Trascript score misZ: 3.3024 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.793

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007175.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERLIN2	NM_007175.8	MANE Select	c.406G>C	p.Val136Leu	missense	Exon 6 of 12	NP_009106.1	A0A384ME54
	ERLIN2	NM_001362878.2		c.406G>C	p.Val136Leu	missense	Exon 6 of 12	NP_001349807.1	A0A384ME54
	ERLIN2	NM_001003790.4		c.406G>C	p.Val136Leu	missense	Exon 6 of 7	NP_001003790.1	O94905-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERLIN2	ENST00000519638.3	TSL:2 MANE Select	c.406G>C	p.Val136Leu	missense	Exon 6 of 12	ENSP00000428112.1	O94905-1
	ERLIN2	ENST00000335171.10	TSL:1	c.406G>C	p.Val136Leu	missense	Exon 6 of 7	ENSP00000335220.6	O94905-2
	ERLIN2	ENST00000963384.1		c.496G>C	p.Val166Leu	missense	Exon 5 of 11	ENSP00000633443.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	ERLIN2-related disorder (1)
-	1	-	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		10
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.58		Gain of helix (P = 0.2294)
MVP		0.97
MPC		2.2
ClinPred		0.97	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.56
gMVP		0.92
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs1338086200; hg19: chr8-37602196;