rs61743561

chr6-43186049-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_015089.4(CUL9):c.845G>A(p.Gly282Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0206 in 1,614,214 control chromosomes in the GnomAD database, including 455 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (25 hom., cov: 32)
  • Exomes 𝑓: 0.021 (430 hom.)
• Consequence: CUL9 NM_015089.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.92

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, CUL9
• BP4: Computational evidence support a benign effect (MetaRNN=0.0033248365).
• BP6: Variant 6-43186049-G-A is Benign according to our data. Variant chr6-43186049-G-A is described in ClinVar as [Benign]. Clinvar id is 3056976.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-43186049-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.015 (2280/152326) while in subpopulation NFE AF= 0.024 (1631/68018). AF 95% confidence interval is 0.023. There are 25 homozygotes in gnomad4. There are 1032 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 25 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUL9	NM_015089.4	c.845G>A	p.Gly282Glu	missense_variant	4/41	ENST00000252050.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUL9	ENST00000252050.9	c.845G>A	p.Gly282Glu	missense_variant	4/41	5	NM_015089.4	P2
CUL9	ENST00000372647.6	c.845G>A	p.Gly282Glu	missense_variant	4/41	1		A2
CUL9	ENST00000451399.5	n.920G>A		non_coding_transcript_exon_variant	4/5	2
CUL9	ENST00000515773.5	n.920G>A		non_coding_transcript_exon_variant	4/40	2

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2281 AN: 152208 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00441

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.0122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0240

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.0149 AC: 3753 AN: 251442 Hom.: 45 AF XY: 0.0162 AC XY: 2202 AN XY: 135916

Gnomad AFR exome AF: 0.00369

Gnomad AMR exome AF: 0.00830

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0138

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.0229

Gnomad OTH exome AF: 0.0144

GnomAD4 exome AF: 0.0211 AC: 30919 AN: 1461888 Hom.: 430 Cov.: 32 AF XY: 0.0210 AC XY: 15255 AN XY: 727246

Gnomad4 AFR exome AF: 0.00338

Gnomad4 AMR exome AF: 0.00910

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0134

Gnomad4 FIN exome AF: 0.0138

Gnomad4 NFE exome AF: 0.0247

Gnomad4 OTH exome AF: 0.0172

GnomAD4 genome AF: 0.0150 AC: 2280 AN: 152326 Hom.: 25 Cov.: 32 AF XY: 0.0139 AC XY: 1032 AN XY: 74490

Gnomad4 AFR AF: 0.00440

Gnomad4 AMR AF: 0.0157

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0124

Gnomad4 FIN AF: 0.0122

Gnomad4 NFE AF: 0.0240

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.0196 Hom.: 50

Bravo AF: 0.0139

TwinsUK AF: 0.0229 AC: 85

ALSPAC AF: 0.0239 AC: 92

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0236 AC: 203

ExAC AF: 0.0144 AC: 1752

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CUL9-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 19, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	20
Dann	Benign	0.72
DEOGEN2	Benign	0.060	T;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.61	T;T
MetaRNN	Benign	0.0033	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.84	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.040	N;N
REVEL	Benign	0.072
Sift	Benign	0.18	T;T
Sift4G	Benign	0.93	T;T
Polyphen		0.0030	B;B
Vest4		0.066
MPC		0.96
ClinPred		0.013	T
GERP RS		4.4
Varity_R		0.034
gMVP		0.25

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

Other links and lift over

dbSNP: rs61743561; hg19: chr6-43153787; COSMIC: COSV99037415; COSMIC: COSV99037415;