X-56565446-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_013444.4(UBQLN2):c.1573C>G(p.Pro525Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000126 in 1,194,329 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P525S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000013 ( 0 hom. 4 hem. )

Consequence

UBQLN2
NM_013444.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.0910

Publications

22 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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07153532).

BS2

High AC in GnomAdExome4 at 14 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBQLN2	NM_013444.4 link	c.1573C>G	p.Pro525Ala	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.1573C>G	p.Pro525Ala	missense_variant	Exon 1 of 1	6	NM_013444.4	ENSP00000345195.5		Q9UHD9

Frequencies

GnomAD3 genomes

AF:

0.00000890

AC:

AN:

112368

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000273

AC:

AN:

146519

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000176

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000164

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000129

AC:

AN:

1081961

Hom.:

Cov.:

AF XY:

0.0000113

AC XY:

AN XY:

352503

show subpopulations

African (AFR)

AF:

0.0000385

AC:

AN:

25977

American (AMR)

AF:

0.00

AC:

AN:

32770

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19056

East Asian (EAS)

AF:

0.0000683

AC:

AN:

29288

South Asian (SAS)

AF:

0.00

AC:

AN:

52374

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39307

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4119

European-Non Finnish (NFE)

AF:

0.0000132

AC:

AN:

833609

Other (OTH)

AF:

0.00

AC:

AN:

45461

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000890

AC:

AN:

112368

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34514

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30877

American (AMR)

AF:

0.00

AC:

AN:

10754

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3539

South Asian (SAS)

AF:

0.00

AC:

AN:

2741

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6213

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53155

Other (OTH)

AF:

0.00

AC:

AN:

1516

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000251

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Amyotrophic lateral sclerosis type 15

Uncertain:1

Nov 11, 2024

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 alanine, which is neutral and non-polar, at codon 525 of the UBQLN2 protein (p.Pro525Ala). This variant is present in population databases (rs369947678, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with UBQLN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 2145223). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

not provided

Uncertain:1

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

UBQLN2: PM5:Supporting, BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.029

FATHMM_MKL

Benign

0.19

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.072

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.23

PhyloP100

-0.091

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.90

REVEL

Benign

0.14

Sift

Benign

0.22

Sift4G

Benign

0.28

Polyphen

0.022

Vest4

0.41

MutPred

0.22

Loss of catalytic residue at P524 (P = 0.0218);

MVP

0.69

MPC

0.46

ClinPred

0.0058

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.054

gMVP

0.71

Mutation Taster

=87/13

polymorphism

(source)

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

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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