X-56564841-C-T

Variant names:

• chrX-56564841-C-T
• rs1555977386
• NM_013444.4:c.968C>T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_013444.4(UBQLN2):​c.968C>T​(p.Pro323Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,097,963 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P323P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000010 (0 hom. 2 hem.)
• Consequence: UBQLN2 NM_013444.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.69
• Publications: 0 publications found

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, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.27138764).
• BS2: High AC in GnomAdExome4 at 11 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBQLN2	NM_013444.4	c.968C>T	p.Pro323Leu	missense_variant	Exon 1 of 1	ENST00000338222.7	NP_038472.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBQLN2	ENST00000338222.7	c.968C>T	p.Pro323Leu	missense_variant	Exon 1 of 1	6	NM_013444.4	ENSP00000345195.5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.0000100 AC: 11 AN: 1097963 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 2 AN XY: 363317

African (AFR) AF: 0.00 AC: 0 AN: 26400

American (AMR) AF: 0.00 AC: 0 AN: 35178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54082

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.0000119 AC: 10 AN: 841972

Other (OTH) AF: 0.0000217 AC: 1 AN: 46089

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Amyotrophic lateral sclerosis type 15 Uncertain:1

Dec 16, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 323 of the UBQLN2 protein (p.Pro323Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. This variant has not been reported in the literature in individuals with UBQLN2-related disease. 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	0.00023	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.064	T
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.45	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.7
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.34
Sift	Benign	0.033	D
Sift4G	Uncertain	0.060	T
Polyphen		0.90	P
Vest4		0.18
MutPred		0.16		Loss of glycosylation at P323 (P = 0.0059);
MVP		0.72
MPC		0.49
ClinPred		0.70	D
GERP RS		4.0
Varity_R		0.12
gMVP		0.72
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs1555977386; hg19: chrX-56591274;