NM_013444.4:c.1516C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PM5PP5_Moderate

The NM_013444.4(UBQLN2):​c.1516C>A​(p.Pro506Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P506L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 24)

Consequence

UBQLN2
NM_013444.4 missense

Scores

1
6
10

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 1.15

Publications

46 publications found
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]
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

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1
In a region_of_interest 12 X 3 AA tandem repeats of P-X-X (size 35) in uniprot entity UBQL2_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_013444.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrX-56565390-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 2630374.Status of the report is criteria_provided_single_submitter, 1 stars.
PP5
Variant X-56565389-C-A is Pathogenic according to our data. Variant chrX-56565389-C-A is described in CliVar as Pathogenic. Clinvar id is 29952.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-56565389-C-A is described in CliVar as Pathogenic. Clinvar id is 29952.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
UBQLN2NM_013444.4 linkc.1516C>A p.Pro506Thr 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.1516C>A p.Pro506Thr missense_variant Exon 1 of 1 6 NM_013444.4 ENSP00000345195.5 Q9UHD9

Frequencies

GnomAD3 genomes
Cov.:
24
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
24

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 15 Pathogenic:2
Mar 02, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 506 of the UBQLN2 protein (p.Pro506Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 21857683). ClinVar contains an entry for this variant (Variation ID: 29952). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects UBQLN2 function (PMID: 21857683, 25616961, 26075709, 26152284, 27477512, 27834214, 30333186). This variant disrupts the p.Pro506 amino acid residue in UBQLN2. Other variant(s) that disrupt this residue have been observed in individuals with UBQLN2-related conditions (PMID: 23138764, 28716533), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Aug 21, 2011
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.51
BayesDel_addAF
Pathogenic
0.24
D
BayesDel_noAF
Uncertain
0.11
CADD
Benign
21
DANN
Benign
0.85
DEOGEN2
Benign
0.025
T
FATHMM_MKL
Benign
0.13
N
LIST_S2
Benign
0.74
T
M_CAP
Uncertain
0.21
D
MetaRNN
Uncertain
0.48
T
MetaSVM
Benign
-0.63
T
MutationAssessor
Benign
0.0
N
PhyloP100
1.1
PrimateAI
Uncertain
0.79
T
PROVEAN
Benign
0.17
N
REVEL
Uncertain
0.51
Sift
Benign
0.26
T
Sift4G
Benign
0.11
T
Polyphen
0.052
B
Vest4
0.76
MutPred
0.33
Gain of glycosylation at P506 (P = 0.0037);
MVP
1.0
MPC
0.53
ClinPred
0.11
T
GERP RS
4.2
Varity_R
0.12
gMVP
0.81
Mutation Taster
=30/70
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387906711; hg19: chrX-56591822; API