chrX-56565256-G-A

Variant names:

• chrX-56565256-G-A
• rs142250604
• NM_013444.4:c.1383G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_013444.4(UBQLN2):​c.1383G>A​(p.Gly461Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00352 in 1,210,925 control chromosomes in the GnomAD database, including 7 homozygotes. There are 1,407 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (0 hom., 127 hem., cov: 23)
  • Exomes 𝑓: 0.0036 (7 hom. 1280 hem.)
• Consequence: UBQLN2 NM_013444.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.194
• Publications: 1 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant X-56565256-G-A is Benign according to our data. Variant chrX-56565256-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 368609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.194 with no splicing effect.
• BS2: High AC in GnomAd4 at 352 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.1383G>A	p.Gly461Gly	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.1383G>A	p.Gly461Gly	synonymous	Exon 1 of 1	ENSP00000345195.5	Q9UHD9

Frequencies

GnomAD3 genomes AF: 0.00312 AC: 352 AN: 112734 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000580

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00306

Gnomad ASJ AF: 0.00226

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000712

Gnomad FIN AF: 0.0195

Gnomad MID AF: 0.00833

Gnomad NFE AF: 0.00310

Gnomad OTH AF: 0.00329

GnomAD2 exomes AF: 0.00367 AC: 673 AN: 183302 AF XY: 0.00382

Gnomad AFR exome AF: 0.000533

Gnomad AMR exome AF: 0.000912

Gnomad ASJ exome AF: 0.00240

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0184

Gnomad NFE exome AF: 0.00351

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.00356 AC: 3911 AN: 1098137 Hom.: 7 Cov.: 31 AF XY: 0.00352 AC XY: 1280 AN XY: 363497

African (AFR) AF: 0.000455 AC: 12 AN: 26402

American (AMR) AF: 0.00145 AC: 51 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00165 AC: 32 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00157 AC: 85 AN: 54137

European-Finnish (FIN) AF: 0.0171 AC: 691 AN: 40517

Middle Eastern (MID) AF: 0.00387 AC: 16 AN: 4134

European-Non Finnish (NFE) AF: 0.00341 AC: 2875 AN: 842064

Other (OTH) AF: 0.00323 AC: 149 AN: 46087

GnomAD4 genome AF: 0.00312 AC: 352 AN: 112788 Hom.: 0 Cov.: 23 AF XY: 0.00363 AC XY: 127 AN XY: 34950

African (AFR) AF: 0.000579 AC: 18 AN: 31107

American (AMR) AF: 0.00306 AC: 33 AN: 10790

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 6 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3554

South Asian (SAS) AF: 0.000714 AC: 2 AN: 2802

European-Finnish (FIN) AF: 0.0195 AC: 121 AN: 6201

Middle Eastern (MID) AF: 0.00913 AC: 2 AN: 219

European-Non Finnish (NFE) AF: 0.00310 AC: 165 AN: 53236

Other (OTH) AF: 0.00325 AC: 5 AN: 1539

Alfa AF: 0.00284 Hom.: 36

Bravo AF: 0.00238

EpiCase AF: 0.00485

EpiControl AF: 0.00421

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	8.7
DANN	Benign	0.60
PhyloP100		0.19
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: rs142250604; hg19: chrX-56591689;