NM_013444.4:c.1516C>A

Variant names:

• chrX-56565389-C-A
• rs387906711
• NM_013444.4:c.1516C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.15
• Publications: 46 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: 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
UBQLN2	NM_013444.4	c.1516C>A	p.Pro506Thr	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.1516C>A	p.Pro506Thr	missense_variant	Exon 1 of 1	6	NM_013444.4	ENSP00000345195.5

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

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

Other links and lift over

dbSNP: rs387906711; hg19: chrX-56591822;