rs142250604

chrX-56565256-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_013444.4(UBQLN2):c.1383G>A(p.Gly461=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00352 in 1,210,925 control chromosomes in the GnomAD database, including 7 homozygotes. There are 1,407 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., 127 hem., cov: 23)
  • Exomes 𝑓: 0.0036 (7 hom. 1280 hem.)
• Consequence: UBQLN2 NM_013444.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.194

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant X-56565256-G-A is Benign according to our data. Variant chrX-56565256-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 368609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-56565256-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.194 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00312 (352/112788) while in subpopulation NFE AF= 0.0031 (165/53236). AF 95% confidence interval is 0.00271. There are 0 homozygotes in gnomad4. There are 127 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 127 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBQLN2	NM_013444.4	c.1383G>A	p.Gly461=	synonymous_variant	1/1	ENST00000338222.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBQLN2	ENST00000338222.7	c.1383G>A	p.Gly461=	synonymous_variant	1/1		NM_013444.4	P1

Frequencies

GnomAD3 genomes AF: 0.00312 AC: 352 AN: 112734 Hom.: 0 Cov.: 23 AF XY: 0.00364 AC XY: 127 AN XY: 34886

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00306

Gnomad ASJ AF: 0.00226

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000712

Gnomad FIN AF: 0.0195

Gnomad MID AF: 0.00833

Gnomad NFE AF: 0.00310

Gnomad OTH AF: 0.00329

GnomAD3 exomes AF: 0.00367 AC: 673 AN: 183302 Hom.: 1 AF XY: 0.00382 AC XY: 259 AN XY: 67752

Gnomad AFR exome AF: 0.000533

Gnomad AMR exome AF: 0.000912

Gnomad ASJ exome AF: 0.00240

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00147

Gnomad FIN exome AF: 0.0184

Gnomad NFE exome AF: 0.00351

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.00356 AC: 3911 AN: 1098137 Hom.: 7 Cov.: 31 AF XY: 0.00352 AC XY: 1280 AN XY: 363497

Gnomad4 AFR exome AF: 0.000455

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00165

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00157

Gnomad4 FIN exome AF: 0.0171

Gnomad4 NFE exome AF: 0.00341

Gnomad4 OTH exome AF: 0.00323

GnomAD4 genome AF: 0.00312 AC: 352 AN: 112788 Hom.: 0 Cov.: 23 AF XY: 0.00363 AC XY: 127 AN XY: 34950

Gnomad4 AFR AF: 0.000579

Gnomad4 AMR AF: 0.00306

Gnomad4 ASJ AF: 0.00226

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000714

Gnomad4 FIN AF: 0.0195

Gnomad4 NFE AF: 0.00310

Gnomad4 OTH AF: 0.00325

Alfa AF: 0.00284 Hom.: 36

Bravo AF: 0.00238

EpiCase AF: 0.00485

EpiControl AF: 0.00421

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Amyotrophic lateral sclerosis type 15 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 08, 2021	- -
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	Invitae	Jan 31, 2024	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 22, 2020

- -

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	-0.67
Cadd	Benign	8.7
Dann	Benign	0.60

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: rs142250604; hg19: chrX-56591689;