rs142722211

Positions:

• chr8-37753526-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_007175.8(ERLIN2):​c.816T>C​(p.Asn272=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000688 in 1,613,716 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00036 (1 hom.)
• Consequence: ERLIN2 NM_007175.8 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.802

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 8-37753526-T-C is Benign according to our data. Variant chr8-37753526-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 458245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.802 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00384 (584/152210) while in subpopulation AFR AF= 0.0133 (554/41522). AF 95% confidence interval is 0.0124. There are 3 homozygotes in gnomad4. There are 293 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERLIN2	NM_007175.8	c.816T>C	p.Asn272=	synonymous_variant	11/12	ENST00000519638.3	NP_009106.1
ERLIN2	NM_001362878.2	c.816T>C	p.Asn272=	synonymous_variant	11/12		NP_001349807.1
ERLIN2	XM_047421307.1	c.816T>C	p.Asn272=	synonymous_variant	12/13		XP_047277263.1
ERLIN2	XM_047421308.1	c.570T>C	p.Asn190=	synonymous_variant	8/9		XP_047277264.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERLIN2	ENST00000519638.3	c.816T>C	p.Asn272=	synonymous_variant	11/12	2	NM_007175.8	ENSP00000428112	P1
ERLIN2	ENST00000521644.5	c.816T>C	p.Asn272=	synonymous_variant	11/12	5		ENSP00000429621

Frequencies

GnomAD3 genomes AF: 0.00382 AC: 581 AN: 152092 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.000979 AC: 246 AN: 251240 Hom.: 3 AF XY: 0.000729 AC XY: 99 AN XY: 135798

Gnomad AFR exome AF: 0.0134

Gnomad AMR exome AF: 0.000463

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: 0.0000616

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000360 AC: 526 AN: 1461506 Hom.: 1 Cov.: 31 AF XY: 0.000304 AC XY: 221 AN XY: 727084

Gnomad4 AFR exome AF: 0.0128

Gnomad4 AMR exome AF: 0.000671

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: 0.0000144

Gnomad4 OTH exome AF: 0.000778

GnomAD4 genome AF: 0.00384 AC: 584 AN: 152210 Hom.: 3 Cov.: 33 AF XY: 0.00394 AC XY: 293 AN XY: 74414

Gnomad4 AFR AF: 0.0133

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00195 Hom.: 0

Bravo AF: 0.00411

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2021	- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 18, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	3.8
DANN	Benign	0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs142722211; hg19: chr8-37611044;