chrX-56563953-C-T

Variant names:

• chrX-56563953-C-T
• rs1442285695
• NM_013444.4:c.80C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_013444.4(UBQLN2):​c.80C>T​(p.Pro27Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000517 in 1,161,267 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000029 (0 hom. 1 hem.)
• Consequence: UBQLN2 NM_013444.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.171
• 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, Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae)
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000298134 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.060482055).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013444.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBQLN2	NM_013444.4	MANE Select	c.80C>T	p.Pro27Leu	missense	Exon 1 of 1	NP_038472.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBQLN2	ENST00000338222.7	TSL:6 MANE Select	c.80C>T	p.Pro27Leu	missense	Exon 1 of 1	ENSP00000345195.5	Q9UHD9
	ENSG00000298134	ENST00000753204.1		n.148+178G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000266 AC: 3 AN: 112762 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000964

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000286 AC: 3 AN: 1048505 Hom.: 0 Cov.: 30 AF XY: 0.00000295 AC XY: 1 AN XY: 338649

African (AFR) AF: 0.0000799 AC: 2 AN: 25046

American (AMR) AF: 0.00 AC: 0 AN: 27857

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18379

East Asian (EAS) AF: 0.00 AC: 0 AN: 27449

South Asian (SAS) AF: 0.00 AC: 0 AN: 49467

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36689

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3847

European-Non Finnish (NFE) AF: 0.00000123 AC: 1 AN: 815673

Other (OTH) AF: 0.00 AC: 0 AN: 44098

GnomAD4 genome AF: 0.0000266 AC: 3 AN: 112762 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34912

African (AFR) AF: 0.0000964 AC: 3 AN: 31131

American (AMR) AF: 0.00 AC: 0 AN: 10792

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.00 AC: 0 AN: 3576

South Asian (SAS) AF: 0.00 AC: 0 AN: 2740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53256

Other (OTH) AF: 0.00 AC: 0 AN: 1520

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.9
DANN	Benign	0.92
DEOGEN2	Benign	0.021	T
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.16	T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.17
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.015
Sift	Benign	0.35	T
Sift4G	Benign	0.28	T
Polyphen		0.071	B
Vest4		0.050
MutPred		0.29		Gain of helix (P = 0.0034)
MVP		0.20
MPC		0.48
ClinPred		0.060	T
GERP RS		0.68
PromoterAI		-0.037	Neutral
Varity_R		0.068
gMVP		0.48
Mutation Taster		=98/2	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: rs1442285695; hg19: chrX-56590386;