8-37749793-G-T

Variant names:

• chr8-37749793-G-T
• rs398123002
• NM_007175.8:c.499-1G>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_007175.8(ERLIN2):​c.499-1G>T variant causes a splice acceptor, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ERLIN2 NM_007175.8 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.99
• Publications: 5 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: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 8.1, offset of -23, new splice context is: taccctcactttcccatcAGctg. 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 8-37749793-G-T is Pathogenic according to our data. Variant chr8-37749793-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 92113.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERLIN2	NM_007175.8	c.499-1G>T		splice_acceptor_variant, intron_variant	Intron 7 of 11	ENST00000519638.3	NP_009106.1
ERLIN2	NM_001362878.2	c.499-1G>T		splice_acceptor_variant, intron_variant	Intron 7 of 11		NP_001349807.1
ERLIN2	XM_047421307.1	c.499-1G>T		splice_acceptor_variant, intron_variant	Intron 8 of 12		XP_047277263.1
ERLIN2	XM_047421308.1	c.253-1G>T		splice_acceptor_variant, intron_variant	Intron 4 of 8		XP_047277264.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERLIN2	ENST00000519638.3	c.499-1G>T		splice_acceptor_variant, intron_variant	Intron 7 of 11	2	NM_007175.8	ENSP00000428112.1
ERLIN2	ENST00000521644.5	c.499-1G>T		splice_acceptor_variant, intron_variant	Intron 7 of 11	5		ENSP00000429621.1
ERLIN2	ENST00000518526.5	c.370-1G>T		splice_acceptor_variant, intron_variant	Intron 5 of 7	3		ENSP00000429229.1
ERLIN2	ENST00000521993.3	n.428-1G>T		splice_acceptor_variant, intron_variant	Intron 6 of 6	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hereditary spastic paraplegia 18 Pathogenic:1

Oct 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	35
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0	.;.;.;.
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.2
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.0	.;.;.;.
MetaRNN	Benign	0.0	.;.;.;.
MutationAssessor	Benign	0.0	.;.;.;.
PhyloP100		10
PROVEAN	Benign	0.0	.;.;.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.;.;.
Sift4G	Pathogenic	0.0	.;.;.;.
Vest4		0.0
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.52		Position offset: -22
DS_AL_spliceai		0.99		Position offset: 1

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

Other links and lift over

dbSNP: rs398123002; hg19: chr8-37607311;