chrX-56564841-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_013444.4(UBQLN2):​c.968C>T​(p.Pro323Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,097,963 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P323P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 0.000010 ( 0 hom. 2 hem. )

Consequence

UBQLN2
NM_013444.4 missense

Scores

1
5
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.69
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.27138764).
BS2
High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
UBQLN2NM_013444.4 linkc.968C>T p.Pro323Leu missense_variant Exon 1 of 1 ENST00000338222.7 NP_038472.2 Q9UHD9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
UBQLN2ENST00000338222.7 linkc.968C>T p.Pro323Leu missense_variant Exon 1 of 1 6 NM_013444.4 ENSP00000345195.5 Q9UHD9

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
AF:
0.0000100
AC:
11
AN:
1097963
Hom.:
0
Cov.:
32
AF XY:
0.00000550
AC XY:
2
AN XY:
363317
show subpopulations
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:
0.0000119
Gnomad4 OTH exome
AF:
0.0000217
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 15 Uncertain:1
Dec 16, 2017
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 323 of the UBQLN2 protein (p.Pro323Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant has not been reported in the literature in individuals with UBQLN2-related disease. 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
0.00023
T
BayesDel_noAF
Benign
-0.24
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.064
T
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Benign
0.82
T
M_CAP
Pathogenic
0.45
D
MetaRNN
Benign
0.27
T
MetaSVM
Benign
-0.60
T
MutationAssessor
Uncertain
2.2
M
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-1.4
N
REVEL
Uncertain
0.34
Sift
Benign
0.033
D
Sift4G
Uncertain
0.060
T
Polyphen
0.90
P
Vest4
0.18
MutPred
0.16
Loss of glycosylation at P323 (P = 0.0059);
MVP
0.72
MPC
0.49
ClinPred
0.70
D
GERP RS
4.0
Varity_R
0.12
gMVP
0.72

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555977386; hg19: chrX-56591274; API