Variant 10-35028862-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003591.4(CUL2):c.1565C>T(p.Ala522Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000317 in 1,610,676 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000032 ( 1 hom. )

Consequence

CUL2
NM_003591.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.78

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1634309).

BS2

High AC in GnomAdExome4 at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUL2	NM_003591.4 linkuse as main transcript	c.1565C>T	p.Ala522Val	missense_variant	16/21	ENST00000374749.8	NP_003582.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL2	ENST00000374749.8 linkuse as main transcript	c.1565C>T	p.Ala522Val	missense_variant	16/21	1	NM_003591.4	ENSP00000363881	P3	Q13617-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151940

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250732

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135578

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1458736

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

725716

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000396

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151940

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74190

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000900

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2022

The c.1622C>T (p.A541V) alteration is located in exon 16 (coding exon 16) of the CUL2 gene. This alteration results from a C to T substitution at nucleotide position 1622, causing the alanine (A) at amino acid position 541 to be replaced by a valine (V). 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

0.079

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.42

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

Eigen

Benign

0.0060

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

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

M_CAP

Benign

0.011

MetaRNN

Benign

0.16

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

MetaSVM

Benign

-0.87

MutationAssessor

Benign

-0.14

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

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.93

N;N;N;N;D;.;.

REVEL

Benign

0.14

Sift

Benign

0.32

T;T;T;T;D;.;.

Sift4G

Benign

0.42

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

Polyphen

0.0010

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

Vest4

0.20

MutPred

0.42

Loss of disorder (P = 0.0667);Loss of disorder (P = 0.0667);Loss of disorder (P = 0.0667);Loss of disorder (P = 0.0667);.;Loss of disorder (P = 0.0667);.;

MVP

0.54

MPC

0.80

ClinPred

0.36

GERP RS

6.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.18

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over