dbSNP rs11592567: CUL2:c.-81G>A (chr10-35120441-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000688736.1(CUL2):c.-81G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 151,976 control chromosomes in the GnomAD database, including 7,057 homozygotes. 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: 𝑓 0.29 ( 7057 hom., cov: 32)

Exomes 𝑓: 0.50 ( 0 hom. )

Consequence

CUL2
ENST00000688736.1 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.31

Publications

9 publications found

Variant links:

Genes affected

CUL2 (HGNC:2552): (cullin 2) Enables ubiquitin protein ligase binding activity. Predicted to be involved in SCF-dependent proteasomal ubiquitin-dependent protein catabolic process and protein ubiquitination. Predicted to act upstream of or within protein catabolic process. Located in nucleoplasm. Part of Cul2-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

CUL2 links:

ENSG00000230534 (HGNC:):

ENSG00000230534 links:

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new If you want to explore the variant's impact on the transcript ENST00000688736.1, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.343 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000688736.1. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
CUL2	ENST00000688736.1	c.-81G>A	5_prime_UTR	Exon 2 of 7	ENSP00000510643.1	A0A8I5KWB8
CUL2	ENST00000685421.1	c.-51+6164G>A	intron	N/A	ENSP00000509605.1	A0A8I5KWB8
CUL2	ENST00000686156.1	c.-51+6375G>A	intron	N/A	ENSP00000509166.1	A0A8I5KWB8

Frequencies

GnomAD3 genomes

AF:

0.293

AC:

44479

AN:

151856

Hom.:

7045

Cov.:

show subpopulations

Gnomad AFR

AF:

0.162

Gnomad AMI

AF:

0.257

Gnomad AMR

AF:

0.298

Gnomad ASJ

AF:

0.399

Gnomad EAS

AF:

0.296

Gnomad SAS

AF:

0.348

Gnomad FIN

AF:

0.390

Gnomad MID

AF:

0.307

Gnomad NFE

AF:

0.346

Gnomad OTH

AF:

0.316

GnomAD4 exome

AF:

0.500

AC:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

show subpopulations

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

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.500

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.293

AC:

44524

AN:

151974

Hom.:

7057

Cov.:

AF XY:

0.295

AC XY:

21949

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.162

AC:

6718

AN:

41458

American (AMR)

AF:

0.299

AC:

4562

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.399

AC:

1382

AN:

3466

East Asian (EAS)

AF:

0.296

AC:

1529

AN:

5166

South Asian (SAS)

AF:

0.349

AC:

1681

AN:

4816

European-Finnish (FIN)

AF:

0.390

AC:

4108

AN:

10532

Middle Eastern (MID)

AF:

0.303

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.346

AC:

23541

AN:

67960

Other (OTH)

AF:

0.323

AC:

681

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1612

3224

4836

6448

8060

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

456

912

1368

1824

2280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.302

Hom.:

973

Bravo

AF:

0.279

Asia WGS

AF:

0.344

AC:

1195

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.5

(source)

DANN

Benign

0.68

PhyloP100

-1.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over