rs1554517382

Positions:

• chr8-37749851-ATGTGAGTATAC-ACCTGGCTGTGACCTGGGCTGTGA

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_007175.8(ERLIN2):​c.557_557+10delinsCCTGGCTGTGACCTGGGCTGTGA variant causes a splice donor, splice donor 5th base, coding sequence, intron 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ERLIN2 NM_007175.8 splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.99

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.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.3, offset of -50, new splice context is: cggGTaaca. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-37749852-TGTGAGTATAC-CCTGGCTGTGACCTGGGCTGTGA is Pathogenic according to our data. Variant chr8-37749852-TGTGAGTATAC-CCTGGCTGTGACCTGGGCTGTGA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 435090.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERLIN2	NM_007175.8	c.557_557+10delinsCCTGGCTGTGACCTGGGCTGTGA		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	8/12	ENST00000519638.3	NP_009106.1
ERLIN2	NM_001362878.2	c.557_557+10delinsCCTGGCTGTGACCTGGGCTGTGA		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	8/12		NP_001349807.1
ERLIN2	XM_047421307.1	c.557_557+10delinsCCTGGCTGTGACCTGGGCTGTGA		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	9/13		XP_047277263.1
ERLIN2	XM_047421308.1	c.311_311+10delinsCCTGGCTGTGACCTGGGCTGTGA		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	5/9		XP_047277264.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERLIN2	ENST00000519638.3	c.557_557+10delinsCCTGGCTGTGACCTGGGCTGTGA		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	8/12	2	NM_007175.8	ENSP00000428112	P1
ERLIN2	ENST00000518526.5	c.428_428+10delinsCCTGGCTGTGACCTGGGCTGTGA		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	6/8	3		ENSP00000429229
ERLIN2	ENST00000521644.5	c.557_557+10delinsCCTGGCTGTGACCTGGGCTGTGA		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	8/12	5		ENSP00000429621
ERLIN2	ENST00000521993.3	n.486_496delinsCCTGGCTGTGACCTGGGCTGTGA		non_coding_transcript_exon_variant	7/7	3

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 18 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 24, 2016

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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: rs1554517382; hg19: chr8-37607370;