rs387906712

chrX-56565398-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_013444.4(UBQLN2):c.1525C>T(p.Pro509Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,193,953 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 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 0.000045 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.000014 (0 hom. 7 hem.)
• Consequence: UBQLN2 NM_013444.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 0.730

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12488434).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0000445 (5/112235) while in subpopulation AFR AF= 0.00013 (4/30846). AF 95% confidence interval is 0.0000442. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UBQLN2	NM_013444.4	c.1525C>T	p.Pro509Ser	missense_variant	1/1	ENST00000338222.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UBQLN2	ENST00000338222.7	c.1525C>T	p.Pro509Ser	missense_variant	1/1		NM_013444.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000445 AC: 5 AN: 112235 Hom.: 0 Cov.: 24 AF XY: 0.0000291 AC XY: 1 AN XY: 34405

Gnomad AFR AF: 0.000130

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000203 AC: 3 AN: 148092 Hom.: 0 AF XY: 0.0000217 AC XY: 1 AN XY: 46024

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000486

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000139 AC: 15 AN: 1081718 Hom.: 0 Cov.: 31 AF XY: 0.0000199 AC XY: 7 AN XY: 351714

Gnomad4 AFR exome AF: 0.0000385

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000156

Gnomad4 OTH exome AF: 0.0000220

GnomAD4 genome AF: 0.0000445 AC: 5 AN: 112235 Hom.: 0 Cov.: 24 AF XY: 0.0000291 AC XY: 1 AN XY: 34405

Gnomad4 AFR AF: 0.000130

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.000101 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Amyotrophic lateral sclerosis type 15 Pathogenic:1 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 21, 2011	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 19, 2023	Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 29953). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 21857683). This variant is present in population databases (rs387906712, gnomAD 0.005%), including at least one homozygous and/or hemizygous individual. This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 509 of the UBQLN2 protein (p.Pro509Ser). 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. Experimental studies have shown that this missense change affects UBQLN2 function (PMID: 25616961, 26075709). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Benign	20
Dann	Benign	0.83
DEOGEN2	Benign	0.036	T
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.75	T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	-0.55	N
MutationTaster	Benign	0.88	N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	0.11	N
REVEL	Uncertain	0.45
Sift	Benign	0.14	T
Sift4G	Benign	0.77	T
Polyphen		0.0020	B
Vest4		0.34
MutPred		0.29		Gain of glycosylation at P509 (P = 0.0073);
MVP		0.99
MPC		0.48
ClinPred		0.055	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.084
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs387906712; hg19: chrX-56591831;