rs45559331

chrX-56565334-C-AchrX-56565334-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: -2.79

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]

ACMG classification

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: {Benign=6, Uncertain_significance=1, Likely_benign=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 GnomAd at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBQLN2	NM_013444.4	c.1461C>A	p.Thr487=	synonymous_variant	1/1	ENST00000338222.7

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00601 AC: 675 AN: 112340 Hom.: 7 Cov.: 23 AF XY: 0.00530 AC XY: 183 AN XY: 34496

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.: 9 AF XY: 0.00573 AC XY: 347 AN XY: 60601

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.: 37 Cov.: 32 AF XY: 0.00769 AC XY: 2776 AN XY: 361221

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.: 7 Cov.: 23 AF XY: 0.00530 AC XY: 183 AN XY: 34559

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.: 41

Bravo AF: 0.00634

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:4

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	-	- -
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	- -

not provided Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2017	- -
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	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	Molecular Genetics, Royal Melbourne Hospital	Jun 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	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

Other links and lift over

dbSNP: rs45559331; hg19: chrX-56591767;