rs368687557

Positions:

• chr8-37753482-G-A
• chr8-37753482-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_007175.8(ERLIN2):​c.772G>A​(p.Ala258Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,832 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ERLIN2 NM_007175.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ERLIN2. . Trascript score misZ 3.3024 (greater than threshold 3.09). GenCC has associacion of gene with hereditary spastic paraplegia 18, juvenile primary lateral sclerosis, recessive intellectual disability-motor dysfunction-multiple joint contractures syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERLIN2	NM_007175.8	c.772G>A	p.Ala258Thr	missense_variant	11/12	ENST00000519638.3	NP_009106.1
ERLIN2	NM_001362878.2	c.772G>A	p.Ala258Thr	missense_variant	11/12		NP_001349807.1
ERLIN2	XM_047421307.1	c.772G>A	p.Ala258Thr	missense_variant	12/13		XP_047277263.1
ERLIN2	XM_047421308.1	c.526G>A	p.Ala176Thr	missense_variant	8/9		XP_047277264.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERLIN2	ENST00000519638.3	c.772G>A	p.Ala258Thr	missense_variant	11/12	2	NM_007175.8	ENSP00000428112.1
ERLIN2	ENST00000521644.5	c.772G>A	p.Ala258Thr	missense_variant	11/12	5		ENSP00000429621.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251378 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135856

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461832 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727210

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;T;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	.;D;D
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.57	D;D;D
MetaSVM	Uncertain	0.077	D
MutationAssessor	Uncertain	2.3	M;M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Uncertain	0.46
Sift	Benign	0.050	D;D;D
Sift4G	Benign	0.069	T;T;T
Polyphen		0.99	D;D;.
Vest4		0.89
MutPred		0.33		Gain of phosphorylation at A258 (P = 0.0168);Gain of phosphorylation at A258 (P = 0.0168);Gain of phosphorylation at A258 (P = 0.0168);
MVP		0.92
MPC		0.33
ClinPred		0.95	D
GERP RS		6.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.31
gMVP		0.88

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

LitVar

Other links and lift over

dbSNP: rs368687557; hg19: chr8-37611000;