6-43184628-C-A

Variant names:

• chr6-43184628-C-A
• rs41274928
• NM_015089.4:c.318C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BA1

The NM_015089.4(CUL9):​c.318C>A​(p.Gly106Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0321 in 1,611,800 control chromosomes in the GnomAD database, including 1,129 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.048 (293 hom., cov: 32)
  • Exomes 𝑓: 0.030 (836 hom.)
• Consequence: CUL9 NM_015089.4 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.846
• Publications: 6 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 6-43184628-C-A is Benign according to our data. Variant chr6-43184628-C-A is described in ClinVar as [Benign]. Clinvar id is 3037257.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.846 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL9	NM_015089.4	c.318C>A	p.Gly106Gly	synonymous_variant	Exon 2 of 41	ENST00000252050.9	NP_055904.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL9	ENST00000252050.9	c.318C>A	p.Gly106Gly	synonymous_variant	Exon 2 of 41	5	NM_015089.4	ENSP00000252050.4
CUL9	ENST00000372647.6	c.318C>A	p.Gly106Gly	synonymous_variant	Exon 2 of 41	1		ENSP00000361730.2
CUL9	ENST00000451399.5	n.393C>A		non_coding_transcript_exon_variant	Exon 2 of 5	2
CUL9	ENST00000515773.5	n.393C>A		non_coding_transcript_exon_variant	Exon 2 of 40	2

Frequencies

GnomAD3 genomes AF: 0.0482 AC: 7326 AN: 152146 Hom.: 292 Cov.: 32

Gnomad AFR AF: 0.103

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0246

Gnomad ASJ AF: 0.0276

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.0418

Gnomad FIN AF: 0.0221

Gnomad MID AF: 0.0637

Gnomad NFE AF: 0.0295

Gnomad OTH AF: 0.0416

GnomAD2 exomes AF: 0.0318 AC: 7980 AN: 250992 AF XY: 0.0310

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.0202

Gnomad ASJ exome AF: 0.0291

Gnomad EAS exome AF: 0.00130

Gnomad FIN exome AF: 0.0213

Gnomad NFE exome AF: 0.0300

Gnomad OTH exome AF: 0.0337

GnomAD4 exome AF: 0.0304 AC: 44335 AN: 1459536 Hom.: 836 Cov.: 31 AF XY: 0.0303 AC XY: 22008 AN XY: 725548

African (AFR) AF: 0.111 AC: 3702 AN: 33430

American (AMR) AF: 0.0214 AC: 956 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.0276 AC: 721 AN: 26098

East Asian (EAS) AF: 0.00724 AC: 287 AN: 39618

South Asian (SAS) AF: 0.0347 AC: 2989 AN: 86174

European-Finnish (FIN) AF: 0.0230 AC: 1229 AN: 53384

Middle Eastern (MID) AF: 0.0495 AC: 285 AN: 5756

European-Non Finnish (NFE) AF: 0.0289 AC: 32063 AN: 1110122

Other (OTH) AF: 0.0349 AC: 2103 AN: 60280

GnomAD4 genome AF: 0.0482 AC: 7335 AN: 152264 Hom.: 293 Cov.: 32 AF XY: 0.0470 AC XY: 3502 AN XY: 74464

African (AFR) AF: 0.103 AC: 4275 AN: 41554

American (AMR) AF: 0.0246 AC: 376 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0276 AC: 96 AN: 3472

East Asian (EAS) AF: 0.00251 AC: 13 AN: 5178

South Asian (SAS) AF: 0.0416 AC: 201 AN: 4826

European-Finnish (FIN) AF: 0.0221 AC: 235 AN: 10618

Middle Eastern (MID) AF: 0.0685 AC: 20 AN: 292

European-Non Finnish (NFE) AF: 0.0295 AC: 2005 AN: 68006

Other (OTH) AF: 0.0412 AC: 87 AN: 2112

Alfa AF: 0.0376 Hom.: 108

Bravo AF: 0.0511

Asia WGS AF: 0.0270 AC: 94 AN: 3478

EpiCase AF: 0.0307

EpiControl AF: 0.0292

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CUL9-related disorder Benign:1

Dec 20, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
BayesDel_noAF	Benign	-0.38
CADD	Benign	11
DANN	Benign	0.79
PhyloP100		0.85
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs41274928; hg19: chr6-43152366;