rs1554517327

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PM5PP2PP3

The NM_007175.8(ERLIN2):c.452C>G(p.Ala151Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A151V) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ERLIN2
NM_007175.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.58

Publications

0 publications found

Variant links:

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

ERLIN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_007175.8

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-37749586-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 458243.Status of the report is criteria_provided_single_submitter, 1 stars.

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
ERLIN2	NM_007175.8 link	c.452C>G	p.Ala151Gly	missense_variant	Exon 7 of 12	ENST00000519638.3	NP_009106.1
ERLIN2	NM_001362878.2 link	c.452C>G	p.Ala151Gly	missense_variant	Exon 7 of 12		NP_001349807.1
ERLIN2	XM_047421307.1 link	c.452C>G	p.Ala151Gly	missense_variant	Exon 8 of 13		XP_047277263.1
ERLIN2	XM_047421308.1 link	c.206C>G	p.Ala69Gly	missense_variant	Exon 4 of 9		XP_047277264.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
ERLIN2	ENST00000519638.3 link	c.452C>G	p.Ala151Gly	missense_variant	Exon 7 of 12	2	NM_007175.8	ENSP00000428112.1
ERLIN2	ENST00000521644.5 link	c.452C>G	p.Ala151Gly	missense_variant	Exon 7 of 12	5		ENSP00000429621.1
ERLIN2	ENST00000518526.5 link	c.323C>G	p.Ala108Gly	missense_variant	Exon 5 of 8	3		ENSP00000429229.1
ERLIN2	ENST00000521993.3 link	n.381C>G		non_coding_transcript_exon_variant	Exon 6 of 7	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461454

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727074

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111628

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;D;D;D

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;.;D;D

M_CAP

Uncertain

0.13

MetaRNN

Pathogenic

0.82

D;D;D;D

MetaSVM

Pathogenic

0.83

MutationAssessor

Benign

0.0

.;M;M;.

PhyloP100

7.6

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.5

D;D;D;D

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0030

D;D;D;D

Sift4G

Uncertain

0.011

D;D;D;D

Vest4

0.0

ClinPred

0.97

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.59

gMVP

0.69

Mutation Taster

=15/85

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over