NM_013444.4:c.1516C>T

Variant names:

• chrX-56565389-C-T
• rs387906711
• NM_013444.4:c.1516C>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_013444.4(UBQLN2):​c.1516C>T​(p.Pro506Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P506L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 24)
• Consequence: UBQLN2 NM_013444.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.15
• Publications: 46 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a region_of_interest 12 X 3 AA tandem repeats of P-X-X (size 35) in uniprot entity UBQL2_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_013444.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-56565390-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 2630374.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.4094529).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBQLN2	NM_013444.4	c.1516C>T	p.Pro506Ser	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.1516C>T	p.Pro506Ser	missense_variant	Exon 1 of 1	6	NM_013444.4	ENSP00000345195.5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.00000656 AC: 1 AN: 152426 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000156

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Amyotrophic lateral sclerosis type 15 Uncertain:1

Mar 31, 2020

Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.026	T
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.1
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	0.30	N
REVEL	Uncertain	0.48
Sift	Benign	0.84	T
Sift4G	Benign	0.38	T
Polyphen		0.0010	B
Vest4		0.76
MutPred		0.31		Gain of glycosylation at P506 (P = 0.0467);
MVP		0.99
MPC		0.48
ClinPred		0.092	T
GERP RS		4.2
Varity_R		0.071
gMVP		0.80
Mutation Taster		=24/76	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs387906711; hg19: chrX-56591822;