Genetic Variant CUL9:p.Asp9Glu (chr6-43184337-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_015089.4(CUL9):c.27C>A(p.Asp9Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,398,086 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: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CUL9
NM_015089.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.38

Publications

0 publications found

Variant links:

Genes affected

CUL9 (HGNC:15982): (cullin 9) Predicted to enable several functions, including ATP binding activity; metal ion binding activity; and ubiquitin protein ligase binding activity. Involved in microtubule cytoskeleton organization; protein ubiquitination; and regulation of mitotic nuclear division. Located in cytosol. Part of cullin-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

CUL9 links:

Genome browser will be placed here

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=0.040830523).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL9	NM_015089.4 link	c.27C>A	p.Asp9Glu	missense_variant	Exon 2 of 41	ENST00000252050.9	NP_055904.1	Q8IWT3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CUL9	ENST00000252050.9 link	c.27C>A	p.Asp9Glu	missense_variant	Exon 2 of 41	5	NM_015089.4	ENSP00000252050.4	Q8IWT3-1
CUL9	ENST00000372647.6 link	c.27C>A	p.Asp9Glu	missense_variant	Exon 2 of 41	1		ENSP00000361730.2	E9PEZ1
CUL9	ENST00000451399.5 link	n.102C>A		non_coding_transcript_exon_variant	Exon 2 of 5	2
CUL9	ENST00000515773.5 link	n.102C>A		non_coding_transcript_exon_variant	Exon 2 of 40	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000146

AC:

AN:

205536

AF XY:

0.0000182

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000180

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000215

AC:

AN:

1398086

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

686916

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

31970

American (AMR)

AF:

0.00

AC:

AN:

37796

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22820

East Asian (EAS)

AF:

0.0000779

AC:

AN:

38508

South Asian (SAS)

AF:

0.00

AC:

AN:

77820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51478

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5484

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1074626

Other (OTH)

AF:

0.00

AC:

AN:

57584

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.342

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

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

May 05, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.27C>A (p.D9E) alteration is located in exon 2 (coding exon 1) of the CUL9 gene. This alteration results from a C to A substitution at nucleotide position 27, causing the aspartic acid (D) at amino acid position 9 to be replaced by a glutamic acid (E). 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

0.16

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.070

T;T

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.59

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.73

T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.041

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

L;.

PhyloP100

1.4

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.42

N;N

REVEL

Benign

0.053

Sift

Benign

0.86

T;T

Sift4G

Benign

0.60

T;T

Polyphen

0.0

B;B

Vest4

0.24

MutPred

0.19

Gain of disorder (P = 0.0561);Gain of disorder (P = 0.0561);

MVP

0.28

MPC

0.35

ClinPred

0.051

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.036

gMVP

0.18

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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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6-43184337-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