12-124912185-A-G

Variant names:

• chr12-124912185-A-G
• rs71458875
• NM_021009.7:c.1587T>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_021009.7(UBC):​c.1587T>C​(p.Leu529Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0056 (0 hom., cov: 2)
  • Exomes 𝑓: 0.00026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: UBC NM_021009.7 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.32
• Publications: 1 publications found

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

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 12-124912185-A-G is Benign according to our data. Variant chr12-124912185-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3388298.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.32 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021009.7. 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
	UBC	NM_021009.7	MANE Select	c.1587T>C	p.Leu529Leu	synonymous	Exon 2 of 2	NP_066289.3	P0CG48

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBC	ENST00000339647.6	TSL:1 MANE Select	c.1587T>C	p.Leu529Leu	synonymous	Exon 2 of 2	ENSP00000344818.5	P0CG48
	UBC	ENST00000536769.1	TSL:6	c.1587T>C	p.Leu529Leu	synonymous	Exon 1 of 1	ENSP00000441543.1	P0CG48
	UBC	ENST00000874892.1		c.1587T>C	p.Leu529Leu	synonymous	Exon 2 of 2	ENSP00000544951.1

Frequencies

GnomAD3 genomes AF: 0.00572 AC: 27 AN: 4722 Hom.: 0 Cov.: 2

Gnomad AFR AF: 0.00410

Gnomad AMR AF: 0.00188

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0164

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00485

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00231 AC: 72 AN: 31110 AF XY: 0.00192

Gnomad AFR exome AF: 0.00562

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.00286

Gnomad EAS exome AF: 0.00394

Gnomad FIN exome AF: 0.000686

Gnomad NFE exome AF: 0.00212

Gnomad OTH exome AF: 0.00311

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000263 AC: 114 AN: 434116 Hom.: 0 Cov.: 7 AF XY: 0.000293 AC XY: 66 AN XY: 224990

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 12434

American (AMR) AF: 0.000184 AC: 5 AN: 27130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8722

East Asian (EAS) AF: 0.00193 AC: 29 AN: 15038

South Asian (SAS) AF: 0.000892 AC: 28 AN: 31396

European-Finnish (FIN) AF: 0.000125 AC: 3 AN: 24026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1196

European-Non Finnish (NFE) AF: 0.000145 AC: 43 AN: 296856

Other (OTH) AF: 0.000346 AC: 6 AN: 17318

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00560 AC: 27 AN: 4824 Hom.: 0 Cov.: 2 AF XY: 0.00457 AC XY: 14 AN XY: 3066

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00384 AC: 4 AN: 1042

American (AMR) AF: 0.00186 AC: 2 AN: 1078

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 54

East Asian (EAS) AF: 0.00 AC: 0 AN: 186

South Asian (SAS) AF: 0.00 AC: 0 AN: 162

European-Finnish (FIN) AF: 0.0164 AC: 15 AN: 912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 56

European-Non Finnish (NFE) AF: 0.00485 AC: 6 AN: 1238

Other (OTH) AF: 0.00 AC: 0 AN: 96

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.7
DANN	Benign	0.42
PhyloP100		-3.3
Mutation Taster		=64/36	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: rs71458875; hg19: chr12-125396731; COSMIC: COSV60061491; COSMIC: COSV60061491;