Genetic Variant UBQLN2:p.Ser7Arg (chrX-56563894-C-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_013444.4(UBQLN2):c.21C>G(p.Ser7Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000956 in 1,151,136 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000077 ( 0 hom. 1 hem. )

Consequence

UBQLN2
NM_013444.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.542

Publications

0 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, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
amyotrophic lateral sclerosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

UBQLN2 links:

ENSG00000298134 (HGNC:):

ENSG00000298134 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.056657195).

BS2

High AC in GnomAdExome4 at 8 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013444.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBQLN2	NM_013444.4	MANE Select	c.21C>G	p.Ser7Arg	missense	Exon 1 of 1	NP_038472.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBQLN2	ENST00000338222.7	TSL:6 MANE Select	c.21C>G	p.Ser7Arg	missense	Exon 1 of 1	ENSP00000345195.5	Q9UHD9
	ENSG00000298134	ENST00000753204.1		n.148+237G>C		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000266

AC:

AN:

112755

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000278

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000787

AC:

AN:

101671

AF XY:

0.0000427

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000770

AC:

AN:

1038333

Hom.:

Cov.:

AF XY:

0.00000305

AC XY:

AN XY:

327645

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24717

American (AMR)

AF:

0.000291

AC:

AN:

27480

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16485

East Asian (EAS)

AF:

0.00

AC:

AN:

28878

South Asian (SAS)

AF:

0.00

AC:

AN:

46046

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36314

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3025

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

812055

Other (OTH)

AF:

0.00

AC:

AN:

43333

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

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:

0.0000266

AC:

AN:

112803

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34971

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31181

American (AMR)

AF:

0.000278

AC:

AN:

10802

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

3553

South Asian (SAS)

AF:

0.00

AC:

AN:

2767

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6165

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53235

Other (OTH)

AF:

0.00

AC:

AN:

1545

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000457

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Amyotrophic lateral sclerosis type 15 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.56

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.025

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.79

M_CAP

Benign

0.044

MetaRNN

Benign

0.057

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

PhyloP100

0.54

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.73

REVEL

Benign

0.13

Sift

Uncertain

0.028

Sift4G

Uncertain

0.057

Polyphen

0.069

Vest4

0.27

MutPred

0.11

Loss of phosphorylation at S7 (P = 0.005)

MVP

0.37

MPC

0.53

ClinPred

0.079

GERP RS

3.9

PromoterAI

0.026

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.26

gMVP

0.62

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over