Genetic Variant UBB:p.Lys215Lys (chr17-16382552-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_018955.4(UBB):c.645A>G(p.Lys215Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 129,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

UBB
NM_018955.4 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0360

Variant links:

Genes affected

UBB (HGNC:12463): (ubiquitin B) This gene encodes ubiquitin, one of the most conserved proteins known. Ubiquitin has a major role in targeting cellular proteins for degradation by the 26S proteosome. It is also involved in the maintenance of chromatin structure, the regulation of gene expression, and the stress response. Ubiquitin is synthesized as a precursor protein consisting of either polyubiquitin chains or a single ubiquitin moiety fused to an unrelated protein. This gene consists of three direct repeats of the ubiquitin coding sequence with no spacer sequence. Consequently, the protein is expressed as a polyubiquitin precursor with a final amino acid after the last repeat. An aberrant form of this protein has been detected in patients with Alzheimer's disease and Down syndrome. Pseudogenes of this gene are located on chromosomes 1, 2, 13, and 17. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

UBB links:

ENSG00000265401 (HGNC:):

ENSG00000265401 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 17-16382552-A-G is Benign according to our data. Variant chr17-16382552-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 720176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.036 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0177 (2297/129722) while in subpopulation EAS AF= 0.0298 (125/4198). AF 95% confidence interval is 0.0255. There are 0 homozygotes in gnomad4. There are 1023 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2297 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UBB	NM_018955.4 link	c.645A>G	p.Lys215Lys	synonymous_variant	Exon 2 of 2	ENST00000302182.8	NP_061828.1	P0CG47Q5U5U6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UBB	ENST00000302182.8 link	c.645A>G	p.Lys215Lys	synonymous_variant	Exon 2 of 2	1	NM_018955.4	ENSP00000304697.3		P0CG47

Frequencies

GnomAD3 genomes

AF:

0.0178

AC:

2305

AN:

129636

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0225

Gnomad AMI

AF:

0.0427

Gnomad AMR

AF:

0.0125

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.0297

Gnomad SAS

AF:

0.0180

Gnomad FIN

AF:

0.0157

Gnomad MID

AF:

0.118

Gnomad NFE

AF:

0.0153

Gnomad OTH

AF:

0.0187

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000398

AC:

566

AN:

1421210

Hom.:

Cov.:

AF XY:

0.000371

AC XY:

262

AN XY:

707030

show subpopulations

Gnomad4 AFR exome

AF:

0.00113

Gnomad4 AMR exome

AF:

0.00442

Gnomad4 ASJ exome

AF:

0.000325

Gnomad4 EAS exome

AF:

0.00189

Gnomad4 SAS exome

AF:

0.000919

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.000161

Gnomad4 OTH exome

AF:

0.000551

GnomAD4 genome

AF:

0.0177

AC:

2297

AN:

129722

Hom.:

Cov.:

AF XY:

0.0160

AC XY:

1023

AN XY:

64024

show subpopulations

Gnomad4 AFR

AF:

0.0224

Gnomad4 AMR

AF:

0.0125

Gnomad4 ASJ

AF:

0.0115

Gnomad4 EAS

AF:

0.0298

Gnomad4 SAS

AF:

0.0181

Gnomad4 FIN

AF:

0.0157

Gnomad4 NFE

AF:

0.0153

Gnomad4 OTH

AF:

0.0180

Alfa

AF:

0.0464

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.70

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over