Genetic Variant CUL2:p.Met335Ile (chr10-35033271-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_003591.4(CUL2):c.1005G>A(p.Met335Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00491 in 1,606,670 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M335V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0042 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0050 ( 35 hom. )

Consequence

CUL2
NM_003591.4 missense, splice_region

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.89

Publications

12 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008678585).

BP6

Variant 10-35033271-C-T is Benign according to our data. Variant chr10-35033271-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3904831.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 635 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL2	NM_003591.4 link	c.1005G>A	p.Met335Ile	missense_variant, splice_region_variant	Exon 11 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.1005G>A	p.Met335Ile	missense_variant, splice_region_variant	Exon 11 of 21	1	NM_003591.4	ENSP00000363881.3		Q13617-1

Frequencies

GnomAD3 genomes

AF:

0.00418

AC:

635

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00239

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00328

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00580

Gnomad FIN

AF:

0.00217

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00571

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00423

AC:

1061

AN:

250562

AF XY:

0.00448

show subpopulations

Gnomad AFR exome

AF:

0.00192

Gnomad AMR exome

AF:

0.00125

Gnomad ASJ exome

AF:

0.0112

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00294

Gnomad NFE exome

AF:

0.00550

Gnomad OTH exome

AF:

0.00443

GnomAD4 exome

AF:

0.00499

AC:

7253

AN:

1454462

Hom.:

Cov.:

AF XY:

0.00505

AC XY:

3655

AN XY:

724016

show subpopulations

African (AFR)

AF:

0.00189

AC:

AN:

33362

American (AMR)

AF:

0.00136

AC:

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.0109

AC:

285

AN:

26076

East Asian (EAS)

AF:

0.0000758

AC:

AN:

39574

South Asian (SAS)

AF:

0.00554

AC:

477

AN:

86114

European-Finnish (FIN)

AF:

0.00299

AC:

159

AN:

53164

Middle Eastern (MID)

AF:

0.00226

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00537

AC:

5933

AN:

1105578

Other (OTH)

AF:

0.00431

AC:

259

AN:

60148

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

291

583

874

1166

1457

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00417

AC:

635

AN:

152208

Hom.:

Cov.:

AF XY:

0.00360

AC XY:

268

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.00238

AC:

AN:

41544

American (AMR)

AF:

0.00327

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0107

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00580

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00217

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00571

AC:

388

AN:

68000

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

131

164

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00583

Hom.:

Bravo

AF:

0.00399

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.00512

AC:

ExAC

AF:

0.00434

AC:

527

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.00595

EpiControl

AF:

0.00528

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CUL2: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.38

.;T;T;T;.;.;.

Eigen

Benign

-0.16

Eigen_PC

Benign

0.16

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

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

M_CAP

Benign

0.076

MetaRNN

Benign

0.0087

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

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-1.9

.;N;N;N;.;.;.

PhyloP100

7.9

PrimateAI

Uncertain

0.70

PROVEAN

Benign

0.68

N;N;N;N;.;.;.

REVEL

Uncertain

0.36

Sift

Benign

0.96

T;T;T;T;.;.;.

Sift4G

Benign

0.98

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

Polyphen

0.0040

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

Vest4

0.62

MutPred

0.51

Loss of disorder (P = 0.0888);Loss of disorder (P = 0.0888);Loss of disorder (P = 0.0888);Loss of disorder (P = 0.0888);.;Loss of disorder (P = 0.0888);.;

MVP

0.91

MPC

1.9

ClinPred

0.062

GERP RS

6.0

Varity_R

0.24

gMVP

0.37

Mutation Taster

=99/1

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

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10-35033271-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over