Genetic Variant CUL2:p.Ala634Ser (chr10-35013788-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003591.4(CUL2):c.1900G>T(p.Ala634Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000332 in 1,507,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000030 ( 0 hom. )

Consequence

CUL2
NM_003591.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.924

Publications

1 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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.060647964).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL2	NM_003591.4 link	c.1900G>T	p.Ala634Ser	missense_variant	Exon 19 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.1900G>T	p.Ala634Ser	missense_variant	Exon 19 of 21	1	NM_003591.4	ENSP00000363881.3		Q13617-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

208796

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000295

AC:

AN:

1355814

Hom.:

Cov.:

AF XY:

0.00000297

AC XY:

AN XY:

673328

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30770

American (AMR)

AF:

0.00

AC:

AN:

34320

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23900

East Asian (EAS)

AF:

0.00

AC:

AN:

38218

South Asian (SAS)

AF:

0.00

AC:

AN:

71990

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49510

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4904

European-Non Finnish (NFE)

AF:

0.00000382

AC:

AN:

1046078

Other (OTH)

AF:

0.00

AC:

AN:

56124

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74310

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10568

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2090

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

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 14, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1957G>T (p.A653S) alteration is located in exon 19 (coding exon 19) of the CUL2 gene. This alteration results from a G to T substitution at nucleotide position 1957, causing the alanine (A) at amino acid position 653 to be replaced by a serine (S). 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

Benign

0.065

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.36

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

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.91

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

M_CAP

Benign

0.039

MetaRNN

Benign

0.061

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

MetaSVM

Benign

-0.79

MutationAssessor

Benign

-0.41

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

PhyloP100

0.92

PrimateAI

Benign

0.40

PROVEAN

Benign

0.040

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

REVEL

Benign

0.062

Sift

Benign

0.66

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

Sift4G

Benign

0.72

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

Polyphen

0.0010

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

Vest4

0.20

MutPred

0.29

Gain of phosphorylation at A634 (P = 0.0068);Gain of phosphorylation at A634 (P = 0.0068);Gain of phosphorylation at A634 (P = 0.0068);Gain of phosphorylation at A634 (P = 0.0068);.;Gain of phosphorylation at A634 (P = 0.0068);.;

MVP

0.50

MPC

0.75

ClinPred

0.37

GERP RS

4.2

Varity_R

0.049

gMVP

0.14

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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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10-35013788-C-A

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