rs181608326

chr8-37749860-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_007175.8(ERLIN2):c.557+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000253 in 1,613,558 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: ERLIN2 NM_007175.8 splice_region, intron
• Scores: Splicing: ADA: 0.0001641
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.119

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 8-37749860-T-C is Benign according to our data. Variant chr8-37749860-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 240724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00129 (196/152294) while in subpopulation AFR AF= 0.0043 (179/41580). AF 95% confidence interval is 0.00379. There are 0 homozygotes in gnomad4. There are 107 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ERLIN2	NM_007175.8	c.557+8T>C		splice_region_variant, intron_variant		ENST00000519638.3
ERLIN2	NM_001362878.2	c.557+8T>C		splice_region_variant, intron_variant
ERLIN2	XM_047421307.1	c.557+8T>C		splice_region_variant, intron_variant
ERLIN2	XM_047421308.1	c.311+8T>C		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ERLIN2	ENST00000519638.3	c.557+8T>C		splice_region_variant, intron_variant		2	NM_007175.8	P1
ERLIN2	ENST00000518526.5	c.428+8T>C		splice_region_variant, intron_variant		3
ERLIN2	ENST00000521644.5	c.557+8T>C		splice_region_variant, intron_variant		5
ERLIN2	ENST00000521993.3	n.494T>C		non_coding_transcript_exon_variant	7/7	3

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 196 AN: 152176 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00432

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000270 AC: 68 AN: 251440 Hom.: 0 AF XY: 0.000221 AC XY: 30 AN XY: 135890

Gnomad AFR exome AF: 0.00388

Gnomad AMR exome AF: 0.0000867

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000145 AC: 212 AN: 1461264 Hom.: 1 Cov.: 31 AF XY: 0.000125 AC XY: 91 AN XY: 726962

Gnomad4 AFR exome AF: 0.00523

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.00129 AC: 196 AN: 152294 Hom.: 0 Cov.: 33 AF XY: 0.00144 AC XY: 107 AN XY: 74462

Gnomad4 AFR AF: 0.00430

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000830 Hom.: 0

Bravo AF: 0.00142

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 12, 2024

- -

ERLIN2-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 28, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
Cadd	Benign	4.2
Dann	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.0
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: rs181608326; hg19: chr8-37607378;