chrX-56565347-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1BP4BS2

The NM_013444.4(UBQLN2):c.1474G>C(p.Val492Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000995 in 1,206,568 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. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 24)

Exomes 𝑓: 0.0000091 ( 0 hom. 4 hem. )

Consequence

UBQLN2
NM_013444.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.24

Publications

1 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 -3 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, 7 uncertain in NM_013444.4

BP4

Computational evidence support a benign effect (MetaRNN=0.2950069).

BS2

High AC in GnomAdExome4 at 10 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBQLN2	NM_013444.4 link	c.1474G>C	p.Val492Leu	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.1474G>C	p.Val492Leu	missense_variant	Exon 1 of 1	6	NM_013444.4	ENSP00000345195.5		Q9UHD9

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112343

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000118

AC:

AN:

169951

AF XY:

0.0000175

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:

0.0000271

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000914

AC:

AN:

1094225

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

360047

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26313

American (AMR)

AF:

0.00

AC:

AN:

34703

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19310

East Asian (EAS)

AF:

0.00

AC:

AN:

30036

South Asian (SAS)

AF:

0.00

AC:

AN:

53616

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40233

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4126

European-Non Finnish (NFE)

AF:

0.0000119

AC:

AN:

839944

Other (OTH)

AF:

0.00

AC:

AN:

45944

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.533

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:

0.0000178

AC:

AN:

112343

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34519

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30902

American (AMR)

AF:

0.00

AC:

AN:

10739

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3552

South Asian (SAS)

AF:

0.00

AC:

AN:

2751

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6167

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000376

AC:

AN:

53151

Other (OTH)

AF:

0.00

AC:

AN:

1503

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.0000189

ExAC

AF:

0.00000826

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 16, 2017

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Amyotrophic lateral sclerosis type 15

Uncertain:1

Jan 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 492 of the UBQLN2 protein (p.Val492Leu). This variant is present in population databases (rs756653207, gnomAD 0.003%), including at least one homozygous and/or hemizygous individual. 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: 448848). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬¨‚Ä†is likely to be tolerated. 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. -

UBQLN2-related disorder

Uncertain:1

Jun 13, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The UBQLN2 c.1474G>C variant is predicted to result in the amino acid substitution p.Val492Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0027% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including 1 hemizygote. 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

0.24

BayesDel_addAF

Uncertain

0.045

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.023

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.37

MetaRNN

Benign

0.30

MetaSVM

Uncertain

0.52

MutationAssessor

Benign

0.34

PhyloP100

1.2

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.15

REVEL

Uncertain

0.30

Sift

Benign

0.30

Sift4G

Benign

0.42

Polyphen

0.95

Vest4

0.10

MutPred

0.30

Loss of loop (P = 0.2237);

MVP

0.91

MPC

0.53

ClinPred

0.24

GERP RS

4.2

Varity_R

0.20

gMVP

0.74

Mutation Taster

=89/11

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