chrX-56565347-G-T

Variant names:

• chrX-56565347-G-T
• rs756653207
• NM_013444.4:c.1474G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_013444.4(UBQLN2):​c.1474G>T​(p.Val492Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: UBQLN2 NM_013444.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.24
• Publications: 1 publications found

Genes affected

UBQLN2 (HGNC:12509): (ubiquilin 2) This gene encodes an ubiquitin-like protein (ubiquilin) that shares high degree of similarity with related products in yeast, rat and frog. Ubiquilins contain a N-terminal ubiquitin-like domain and a C-terminal ubiquitin-associated domain. They physically associate with both proteasomes and ubiquitin ligases; and thus, are thought to functionally link the ubiquitination machinery to the proteasome to affect in vivo protein degradation. This ubiquilin has also been shown to bind the ATPase domain of the Hsp70-like Stch protein. [provided by RefSeq, Oct 2009]

UBQLN2 Gene-Disease associations (from GenCC):

• amyotrophic lateral sclerosis type 15

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 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, 7 uncertain in NM_013444.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28204456).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBQLN2	NM_013444.4	c.1474G>T	p.Val492Leu	missense_variant	Exon 1 of 1	ENST00000338222.7	NP_038472.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBQLN2	ENST00000338222.7	c.1474G>T	p.Val492Leu	missense_variant	Exon 1 of 1	6	NM_013444.4	ENSP00000345195.5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000588 AC: 1 AN: 169951 AF XY: 0.0000175

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.14e-7 AC: 1 AN: 1094225 Hom.: 0 Cov.: 31 AF XY: 0.00000278 AC XY: 1 AN XY: 360047

African (AFR) AF: 0.00 AC: 0 AN: 26313

American (AMR) AF: 0.00 AC: 0 AN: 34703

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19310

East Asian (EAS) AF: 0.00 AC: 0 AN: 30036

South Asian (SAS) AF: 0.0000187 AC: 1 AN: 53616

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40233

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4126

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 839944

Other (OTH) AF: 0.00 AC: 0 AN: 45944

GnomAD4 genome Cov.: 24

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Amyotrophic lateral sclerosis type 15 Uncertain:1

Apr 07, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine with leucine at codon 492 of the UBQLN2 protein (p.Val492Leu). The valine residue is moderately conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs756653207, ExAC 0.01%). This variant has not been reported in the literature in individuals with UBQLN2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.023	T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	0.52	D
MutationAssessor	Benign	0.34	N
PhyloP100		1.2
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.15	N
REVEL	Uncertain	0.29
Sift	Benign	0.30	T
Sift4G	Benign	0.42	T
Polyphen		0.95	P
Vest4		0.10
MutPred		0.30		Loss of loop (P = 0.2237);
MVP		0.91
MPC		0.53
ClinPred		0.28	T
GERP RS		4.2
Varity_R		0.20
gMVP		0.74
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs756653207; hg19: chrX-56591780;