12-124913018-C-T

Position:

• chr12-124913018-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_021009.7(UBC):​c.754G>A​(p.Glu252Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 30)
• Consequence: UBC NM_021009.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.31

Genes affected

UBC (HGNC:12468): (ubiquitin C) This gene represents a ubiquitin gene, ubiquitin C. The encoded protein is a polyubiquitin precursor. Conjugation of ubiquitin monomers or polymers can lead to various effects within a cell, depending on the residues to which ubiquitin is conjugated. Ubiquitination has been associated with protein degradation, DNA repair, cell cycle regulation, kinase modification, endocytosis, and regulation of other cell signaling pathways. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31742287).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UBC	NM_021009.7	c.754G>A	p.Glu252Lys	missense_variant	2/2	ENST00000339647.6	NP_066289.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UBC	ENST00000339647.6	c.754G>A	p.Glu252Lys	missense_variant	2/2	1	NM_021009.7	ENSP00000344818.5
UBC	ENST00000536769.1	c.754G>A	p.Glu252Lys	missense_variant	1/1	6		ENSP00000441543.1
UBC	ENST00000538617.5	c.451+303G>A		intron_variant		5		ENSP00000443053.1
UBC	ENST00000541272.1	c.*17G>A		downstream_gene_variant		5		ENSP00000440205.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 154

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 15, 2024

The c.754G>A (p.E252K) alteration is located in exon 2 (coding exon 1) of the UBC gene. This alteration results from a G to A substitution at nucleotide position 754, causing the glutamic acid (E) at amino acid position 252 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	0.075
Eigen_PC	Benign	0.066
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.77	.;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.2	L;L
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.92	N;N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0040	D;D
Sift4G	Benign	0.15	T;T
Polyphen		0.74	P;P
Vest4		0.34
MutPred		0.42		Loss of helix (P = 0.0072);Loss of helix (P = 0.0072);
MVP		0.90
MPC		1.8
ClinPred		0.78	D
GERP RS		2.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.19
gMVP		0.87

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-125397564;