rs587776893

Positions:

• chr8-37753521-G-GCA

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_007175.8(ERLIN2):​c.812_813insAC​(p.Asn272ProfsTer4) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ERLIN2 NM_007175.8 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.73

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 Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.205 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-37753521-G-GCA is Pathogenic according to our data. Variant chr8-37753521-G-GCA is described in ClinVar as [Pathogenic]. Clinvar id is 30913.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERLIN2	NM_007175.8	c.812_813insAC	p.Asn272ProfsTer4	frameshift_variant	11/12	ENST00000519638.3	NP_009106.1
ERLIN2	NM_001362878.2	c.812_813insAC	p.Asn272ProfsTer4	frameshift_variant	11/12		NP_001349807.1
ERLIN2	XM_047421307.1	c.812_813insAC	p.Asn272ProfsTer4	frameshift_variant	12/13		XP_047277263.1
ERLIN2	XM_047421308.1	c.566_567insAC	p.Asn190ProfsTer4	frameshift_variant	8/9		XP_047277264.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERLIN2	ENST00000519638.3	c.812_813insAC	p.Asn272ProfsTer4	frameshift_variant	11/12	2	NM_007175.8	ENSP00000428112	P1
ERLIN2	ENST00000521644.5	c.812_813insAC	p.Asn272ProfsTer4	frameshift_variant	11/12	5		ENSP00000429621

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hereditary spastic paraplegia 18 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 15, 2011

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs587776893; hg19: chr8-37611039;