NM_013444.4:c.1461C>A

Variant names:

• chrX-56565334-C-A
• rs45559331
• NM_013444.4:c.1461C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_013444.4(UBQLN2):​c.1461C>A​(p.Thr487Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00771 in 1,208,008 control chromosomes in the GnomAD database, including 44 homozygotes. There are 2,959 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0060 (7 hom., 183 hem., cov: 23)
  • Exomes 𝑓: 0.0079 (37 hom. 2776 hem.)
• Consequence: UBQLN2 NM_013444.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: -2.79
• Publications: 3 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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant X-56565334-C-A is Benign according to our data. Variant chrX-56565334-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 260311.
• BP7: Synonymous conserved (PhyloP=-2.79 with no splicing effect.
• BS2: High AC in GnomAd4 at 674 XL,AD gene.

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.1461C>A	p.Thr487Thr	synonymous	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.1461C>A	p.Thr487Thr	synonymous	Exon 1 of 1	ENSP00000345195.5	Q9UHD9

Frequencies

GnomAD3 genomes AF: 0.00601 AC: 675 AN: 112340 Hom.: 7 Cov.: 23

Gnomad AFR AF: 0.00139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00830

Gnomad ASJ AF: 0.00866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00109

Gnomad FIN AF: 0.00341

Gnomad MID AF: 0.00837

Gnomad NFE AF: 0.00901

Gnomad OTH AF: 0.00989

GnomAD2 exomes AF: 0.00595 AC: 1041 AN: 174861 AF XY: 0.00573

Gnomad AFR exome AF: 0.00121

Gnomad AMR exome AF: 0.00369

Gnomad ASJ exome AF: 0.0142

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00463

Gnomad NFE exome AF: 0.00903

Gnomad OTH exome AF: 0.00805

GnomAD4 exome AF: 0.00789 AC: 8641 AN: 1095615 Hom.: 37 Cov.: 32 AF XY: 0.00769 AC XY: 2776 AN XY: 361221

African (AFR) AF: 0.00129 AC: 34 AN: 26350

American (AMR) AF: 0.00421 AC: 147 AN: 34911

Ashkenazi Jewish (ASJ) AF: 0.0125 AC: 241 AN: 19336

East Asian (EAS) AF: 0.00 AC: 0 AN: 30106

South Asian (SAS) AF: 0.00138 AC: 74 AN: 53763

European-Finnish (FIN) AF: 0.00461 AC: 186 AN: 40314

Middle Eastern (MID) AF: 0.0104 AC: 43 AN: 4123

European-Non Finnish (NFE) AF: 0.00899 AC: 7560 AN: 840723

Other (OTH) AF: 0.00774 AC: 356 AN: 45989

GnomAD4 genome AF: 0.00600 AC: 674 AN: 112393 Hom.: 7 Cov.: 23 AF XY: 0.00530 AC XY: 183 AN XY: 34559

African (AFR) AF: 0.00139 AC: 43 AN: 30985

American (AMR) AF: 0.00829 AC: 89 AN: 10732

Ashkenazi Jewish (ASJ) AF: 0.00866 AC: 23 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3536

South Asian (SAS) AF: 0.00109 AC: 3 AN: 2756

European-Finnish (FIN) AF: 0.00341 AC: 21 AN: 6153

Middle Eastern (MID) AF: 0.00459 AC: 1 AN: 218

European-Non Finnish (NFE) AF: 0.00901 AC: 479 AN: 53135

Other (OTH) AF: 0.00977 AC: 15 AN: 1536

Alfa AF: 0.00477 Hom.: 41

Bravo AF: 0.00634

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Amyotrophic lateral sclerosis type 15 (3)
-	1	2	not provided (3)
-	-	1	Amyotrophic Lateral Sclerosis, Dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	1.6
DANN	Benign	0.71
PhyloP100		-2.8
Mutation Taster		=100/0	polymorphism (auto)

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: rs45559331; hg19: chrX-56591767;