Variant 11-108098480-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_003478.6(CUL5):c.2099G>A(p.Arg700Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000626 in 1,597,240 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

CUL5
NM_003478.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.48

Variant links:

Genes affected

CUL5 (HGNC:2556): (cullin 5) 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 cerebral cortex radially oriented cell migration and radial glia guided migration of Purkinje cell. Located in site of DNA damage. Part of Cul5-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

CUL5 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=0.123141795).

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUL5	NM_003478.6 linkuse as main transcript	c.2099G>A	p.Arg700Lys	missense_variant	18/19	ENST00000393094.7	NP_003469.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL5	ENST00000393094.7 linkuse as main transcript	c.2099G>A	p.Arg700Lys	missense_variant	18/19	1	NM_003478.6	ENSP00000376808.2		Q93034
CUL5	ENST00000531427.5 linkuse as main transcript	n.2099G>A		non_coding_transcript_exon_variant	18/20	1		ENSP00000435376.1		Q93034

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151846

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00144

GnomAD3 exomes

AF:

0.00000834

AC:

AN:

239726

Hom.:

AF XY:

0.00000768

AC XY:

AN XY:

130124

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000318

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:

0.00

Gnomad OTH exome

AF:

0.000174

GnomAD4 exome

AF:

0.00000277

AC:

AN:

1445280

Hom.:

Cov.:

AF XY:

0.00000417

AC XY:

AN XY:

719092

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000941

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000395

AC:

AN:

151960

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74246

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00142

Bravo

AF:

0.0000945

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

Dec 17, 2023

The c.2099G>A (p.R700K) alteration is located in exon 18 (coding exon 18) of the CUL5 gene. This alteration results from a G to A substitution at nucleotide position 2099, causing the arginine (R) at amino acid position 700 to be replaced by a lysine (K). 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

0.12

BayesDel_addAF

Uncertain

0.055

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.089

Eigen

Benign

-0.16

Eigen_PC

Benign

0.14

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.027

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.90

MutationAssessor

Benign

-0.59

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

0.36

REVEL

Benign

0.27

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.50

MVP

0.84

MPC

1.1

ClinPred

0.76

GERP RS

5.6

Varity_R

0.51

gMVP

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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