rs2146635566

Variant names:

• chrX-56563929-C-T
• rs2146635566
• NM_013444.4:c.56C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_013444.4(UBQLN2):​c.56C>T​(p.Ala19Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000384 in 1,041,948 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000038 (0 hom. 1 hem.)
• Consequence: UBQLN2 NM_013444.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.24
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21663693).

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.56C>T	p.Ala19Val	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.56C>T	p.Ala19Val	missense	Exon 1 of 1	ENSP00000345195.5	Q9UHD9
	ENSG00000298134	ENST00000753204.1		n.148+202G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000384 AC: 4 AN: 1041948 Hom.: 0 Cov.: 30 AF XY: 0.00000301 AC XY: 1 AN XY: 332094

African (AFR) AF: 0.00 AC: 0 AN: 25017

American (AMR) AF: 0.00 AC: 0 AN: 27578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17687

East Asian (EAS) AF: 0.00 AC: 0 AN: 27807

South Asian (SAS) AF: 0.00 AC: 0 AN: 48076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36465

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3578

European-Non Finnish (NFE) AF: 0.00000493 AC: 4 AN: 812009

Other (OTH) AF: 0.00 AC: 0 AN: 43731

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Amyotrophic lateral sclerosis type 15 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.2
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.066
Sift	Benign	0.15	T
Sift4G	Benign	0.30	T
Polyphen		0.98	D
Vest4		0.17
MutPred		0.20		Loss of glycosylation at P17 (P = 0.1694)
MVP		0.40
MPC		0.47
ClinPred		0.60	D
GERP RS		4.6
PromoterAI		-0.12	Neutral
Varity_R		0.090
gMVP		0.41
Mutation Taster		=94/6	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: rs2146635566; hg19: chrX-56590362;