Genetic Variant CUL2:p.Arg708Gly (chr10-35010427-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_003591.4(CUL2):c.2122A>G(p.Arg708Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,457,654 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R708S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CUL2
NM_003591.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.20

Publications

0 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:

ENSG00000301061 (HGNC:):

ENSG00000301061 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32683322).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL2	NM_003591.4 link	c.2122A>G	p.Arg708Gly	missense_variant	Exon 21 of 21	ENST00000374749.8	NP_003582.2	Q13617-1A0A140VKB1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL2	ENST00000374749.8 link	c.2122A>G	p.Arg708Gly	missense_variant	Exon 21 of 21	1	NM_003591.4	ENSP00000363881.3		Q13617-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1457654

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725096

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33172

American (AMR)

AF:

0.0000227

AC:

AN:

43992

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26030

East Asian (EAS)

AF:

0.00

AC:

AN:

39408

South Asian (SAS)

AF:

0.0000234

AC:

AN:

85608

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110118

Other (OTH)

AF:

0.00

AC:

AN:

60210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 12, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2179A>G (p.R727G) alteration is located in exon 21 (coding exon 21) of the CUL2 gene. This alteration results from a A to G substitution at nucleotide position 2179, causing the arginine (R) at amino acid position 727 to be replaced by a glycine (G). 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

Uncertain

0.56

BayesDel_addAF

Uncertain

0.030

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.82

.;D;D;D;.;.;.

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.037

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

.;.;.;D;D;D;D

M_CAP

Benign

0.047

MetaRNN

Benign

0.33

T;T;T;T;T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.2

.;L;L;L;.;.;.

PhyloP100

4.2

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-3.6

D;D;D;D;.;.;.

REVEL

Uncertain

0.38

Sift

Benign

0.045

D;D;D;D;.;.;.

Sift4G

Benign

0.072

T;T;T;T;T;T;T

Polyphen

0.0010

.;B;B;B;.;.;.

Vest4

0.40

MutPred

0.60

.;Loss of MoRF binding (P = 0.0365);Loss of MoRF binding (P = 0.0365);Loss of MoRF binding (P = 0.0365);.;.;.;

MVP

0.78

MPC

1.1

ClinPred

0.88

GERP RS

3.3

Varity_R

0.62

gMVP

0.34

Mutation Taster

=63/37

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

10-35010427-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over