rs45559331

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_013444.4(UBQLN2):c.1461C>A(p.Thr487=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00771 in 1,208,008 control chromosomes in the GnomAD database, including 44 homozygotes. There are 2,959 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0060 ( 7 hom., 183 hem., cov: 23)

Exomes 𝑓: 0.0079 ( 37 hom. 2776 hem. )

Consequence

UBQLN2
NM_013444.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:10

Conservation

PhyloP100: -2.79

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant X-56565334-C-A is Benign according to our data. Variant chrX-56565334-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260311.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=6, Uncertain_significance=1}. Variant chrX-56565334-C-A is described in Lovd as [Likely_benign]. Variant chrX-56565334-C-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.79 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.006 (674/112393) while in subpopulation NFE AF= 0.00901 (479/53135). AF 95% confidence interval is 0.00835. There are 7 homozygotes in gnomad4. There are 183 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBQLN2	NM_013444.4 linkuse as main transcript	c.1461C>A	p.Thr487=	synonymous_variant	1/1	ENST00000338222.7	NP_038472.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBQLN2	ENST00000338222.7 linkuse as main transcript	c.1461C>A	p.Thr487=	synonymous_variant	1/1		NM_013444.4	ENSP00000345195	P1

Frequencies

GnomAD3 genomes

AF:

0.00601

AC:

675

AN:

112340

Hom.:

Cov.:

AF XY:

0.00530

AC XY:

183

AN XY:

34496

show subpopulations

Gnomad AFR

AF:

0.00139

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00830

Gnomad ASJ

AF:

0.00866

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00109

Gnomad FIN

AF:

0.00341

Gnomad MID

AF:

0.00837

Gnomad NFE

AF:

0.00901

Gnomad OTH

AF:

0.00989

GnomAD3 exomes

AF:

0.00595

AC:

1041

AN:

174861

Hom.:

AF XY:

0.00573

AC XY:

347

AN XY:

60601

show subpopulations

Gnomad AFR exome

AF:

0.00121

Gnomad AMR exome

AF:

0.00369

Gnomad ASJ exome

AF:

0.0142

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00126

Gnomad FIN exome

AF:

0.00463

Gnomad NFE exome

AF:

0.00903

Gnomad OTH exome

AF:

0.00805

GnomAD4 exome

AF:

0.00789

AC:

8641

AN:

1095615

Hom.:

Cov.:

AF XY:

0.00769

AC XY:

2776

AN XY:

361221

show subpopulations

Gnomad4 AFR exome

AF:

0.00129

Gnomad4 AMR exome

AF:

0.00421

Gnomad4 ASJ exome

AF:

0.0125

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00138

Gnomad4 FIN exome

AF:

0.00461

Gnomad4 NFE exome

AF:

0.00899

Gnomad4 OTH exome

AF:

0.00774

GnomAD4 genome

AF:

0.00600

AC:

674

AN:

112393

Hom.:

Cov.:

AF XY:

0.00530

AC XY:

183

AN XY:

34559

show subpopulations

Gnomad4 AFR

AF:

0.00139

Gnomad4 AMR

AF:

0.00829

Gnomad4 ASJ

AF:

0.00866

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00109

Gnomad4 FIN

AF:

0.00341

Gnomad4 NFE

AF:

0.00901

Gnomad4 OTH

AF:

0.00977

Alfa

AF:

0.00477

Hom.:

Bravo

AF:

0.00634

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 25, 2020	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 01, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 02, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Amyotrophic lateral sclerosis type 15

Benign:3

Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Jun 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Amyotrophic Lateral Sclerosis, Dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

1.6

DANN

Benign

0.71

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over