chr8-37749852-TGTGAGTATAC-CCTGGCTGTGACCTGGGCTGTGA

Variant names:

• chr8-37749852-TGTGAGTATAC-CCTGGCTGTGACCTGGGCTGTGA
• rs1554517382
• NM_007175.8:c.557_557+10delTGTGAGTATACinsCCTGGCTGTGACCTGGGCTGTGA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PP2 PP5_Moderate

The NM_007175.8(ERLIN2):​c.557_557+10delTGTGAGTATACinsCCTGGCTGTGACCTGGGCTGTGA​(p.Met186delinsThrTrpLeuTerPro) variant causes a stop gained, splice donor, missense, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ERLIN2 NM_007175.8 stop_gained, splice_donor, missense, splice_region, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.99
• 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 Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Orphanet
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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 recessive intellectual disability-motor dysfunction-multiple joint contractures syndrome, hereditary spastic paraplegia 18, juvenile primary lateral sclerosis.
• 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 VariationId is 435090.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERLIN2	NM_007175.8	c.557_557+10delTGTGAGTATACinsCCTGGCTGTGACCTGGGCTGTGA	p.Met186delinsThrTrpLeuTerPro	stop_gained, splice_donor_variant, missense_variant, splice_region_variant, intron_variant		ENST00000519638.3	NP_009106.1
ERLIN2	NM_001362878.2	c.557_557+10delTGTGAGTATACinsCCTGGCTGTGACCTGGGCTGTGA	p.Met186delinsThrTrpLeuTerPro	stop_gained, splice_donor_variant, missense_variant, splice_region_variant, intron_variant			NP_001349807.1
ERLIN2	XM_047421307.1	c.557_557+10delTGTGAGTATACinsCCTGGCTGTGACCTGGGCTGTGA	p.Met186delinsThrTrpLeuTerPro	stop_gained, splice_donor_variant, missense_variant, splice_region_variant, intron_variant			XP_047277263.1
ERLIN2	XM_047421308.1	c.311_311+10delTGTGAGTATACinsCCTGGCTGTGACCTGGGCTGTGA	p.Met104delinsThrTrpLeuTerPro	stop_gained, splice_donor_variant, missense_variant, splice_region_variant, intron_variant			XP_047277264.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERLIN2	ENST00000519638.3	c.557_557+10delTGTGAGTATACinsCCTGGCTGTGACCTGGGCTGTGA	p.Met186delinsThrTrpLeuTerPro	stop_gained, splice_donor_variant, missense_variant, splice_region_variant, intron_variant		2	NM_007175.8	ENSP00000428112.1
ERLIN2	ENST00000521993.3	n.486_496delTGTGAGTATACinsCCTGGCTGTGACCTGGGCTGTGA		non_coding_transcript_exon_variant	Exon 7 of 7	3
ERLIN2	ENST00000521644.5	c.557_557+10delTGTGAGTATACinsCCTGGCTGTGACCTGGGCTGTGA	p.Met186delinsThrTrpLeuTerPro	stop_gained, splice_donor_variant, missense_variant, splice_region_variant, intron_variant		5		ENSP00000429621.1
ERLIN2	ENST00000518526.5	c.428_428+10delTGTGAGTATACinsCCTGGCTGTGACCTGGGCTGTGA	p.Met143delinsThrTrpLeuTerPro	stop_gained, splice_donor_variant, missense_variant, splice_region_variant, intron_variant		3		ENSP00000429229.1

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

Jun 24, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		10

Splicing

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

Other links and lift over

dbSNP: rs1554517382; hg19: chr8-37607370;