rs387906712

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_013444.4(UBQLN2):c.1525C>T(p.Pro509Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,193,953 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 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. P509P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.000014 ( 0 hom. 7 hem. )

Consequence

UBQLN2
NM_013444.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:2

Conservation

PhyloP100: 0.730

Publications

19 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

UBQLN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 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, 5 uncertain in NM_013444.4

BP4

Computational evidence support a benign effect (MetaRNN=0.12488434).

BS2

High AC in GnomAd4 at 5 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBQLN2	NM_013444.4 link	c.1525C>T	p.Pro509Ser	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
UBQLN2	ENST00000338222.7 link	c.1525C>T	p.Pro509Ser	missense_variant	Exon 1 of 1	6	NM_013444.4	ENSP00000345195.5		Q9UHD9

Frequencies

GnomAD3 genomes

AF:

0.0000445

AC:

AN:

112235

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000203

AC:

AN:

148092

AF XY:

0.0000217

show subpopulations

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:

0.0000486

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000139

AC:

AN:

1081718

Hom.:

Cov.:

AF XY:

0.0000199

AC XY:

AN XY:

351714

show subpopulations

African (AFR)

AF:

0.0000385

AC:

AN:

25989

American (AMR)

AF:

0.00

AC:

AN:

33032

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19089

East Asian (EAS)

AF:

0.00

AC:

AN:

29254

South Asian (SAS)

AF:

0.00

AC:

AN:

52291

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39241

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4102

European-Non Finnish (NFE)

AF:

0.0000156

AC:

AN:

833275

Other (OTH)

AF:

0.0000220

AC:

AN:

45445

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000445

AC:

AN:

112235

Hom.:

Cov.:

AF XY:

0.0000291

AC XY:

AN XY:

34405

show subpopulations

African (AFR)

AF:

0.000130

AC:

AN:

30846

American (AMR)

AF:

0.00

AC:

AN:

10732

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3551

South Asian (SAS)

AF:

0.00

AC:

AN:

2736

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6156

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53121

Other (OTH)

AF:

0.00

AC:

AN:

1516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.000101

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 15

Pathogenic:1Uncertain:1

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 509 of the UBQLN2 protein (p.Pro509Ser). This variant is present in population databases (rs387906712, gnomAD 0.005%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 21857683). ClinVar contains an entry for this variant (Variation ID: 29953). Algorithms developed to predict the effect of variants on gene product 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: 25616961, 26075709). 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. -

Aug 21, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

UBQLN2-related disorder

Uncertain:1

Jan 31, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The UBQLN2 c.1525C>T variant is predicted to result in the amino acid substitution p.Pro509Ser. This variant was reported in an individual with amyotrophic lateral sclerosis (Deng et al. 2011. PubMed ID: 21857683) with functional in vitro studies suggesting this variant impairs protein function (Gilpin et al. 2015. PubMed ID: 25616961; Chang et al. 2015. PubMed ID: 26075709). This variant is reported in 0.0049% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.058

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.036

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.75

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.63

MutationAssessor

Benign

-0.55

PhyloP100

0.73

PrimateAI

Uncertain

0.77

PROVEAN

Benign

0.11

REVEL

Uncertain

0.45

Sift

Benign

0.14

Sift4G

Benign

0.77

Polyphen

0.0020

Vest4

0.34

MutPred

0.29

Gain of glycosylation at P509 (P = 0.0073);

MVP

0.99

MPC

0.48

ClinPred

0.055

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.084

gMVP

0.79

Mutation Taster

=36/64

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over