chr6-43184323-C-T

Variant names:

• chr6-43184323-C-T
• rs375175228
• NM_015089.4:c.13C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015089.4(CUL9):​c.13C>T​(p.Arg5Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,520,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: CUL9 NM_015089.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.40
• Publications: 2 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21799952).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015089.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL9	NM_015089.4	MANE Select	c.13C>T	p.Arg5Trp	missense	Exon 2 of 41	NP_055904.1	Q8IWT3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL9	ENST00000252050.9	TSL:5 MANE Select	c.13C>T	p.Arg5Trp	missense	Exon 2 of 41	ENSP00000252050.4	Q8IWT3-1
	CUL9	ENST00000372647.6	TSL:1	c.13C>T	p.Arg5Trp	missense	Exon 2 of 41	ENSP00000361730.2	E9PEZ1
	CUL9	ENST00000885097.1		c.13C>T	p.Arg5Trp	missense	Exon 3 of 42	ENSP00000555156.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151982 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000452 AC: 8 AN: 177098 AF XY: 0.0000532

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000445

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000592

Gnomad NFE exome AF: 0.0000733

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000132 AC: 18 AN: 1368504 Hom.: 0 Cov.: 30 AF XY: 0.0000194 AC XY: 13 AN XY: 670232

African (AFR) AF: 0.00 AC: 0 AN: 30850

American (AMR) AF: 0.0000316 AC: 1 AN: 31678

Ashkenazi Jewish (ASJ) AF: 0.0000472 AC: 1 AN: 21188

East Asian (EAS) AF: 0.00 AC: 0 AN: 37910

South Asian (SAS) AF: 0.0000274 AC: 2 AN: 73032

European-Finnish (FIN) AF: 0.0000198 AC: 1 AN: 50420

Middle Eastern (MID) AF: 0.000374 AC: 2 AN: 5346

European-Non Finnish (NFE) AF: 0.0000104 AC: 11 AN: 1061726

Other (OTH) AF: 0.00 AC: 0 AN: 56354

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151982 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74198

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

African (AFR) AF: 0.00 AC: 0 AN: 41354

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000328 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000578 AC: 7

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	0.0070
Eigen_PC	Benign	-0.024
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.4
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.28
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.27
MVP		0.58
MPC		0.82
ClinPred		0.55	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.085
gMVP		0.58
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs375175228; hg19: chr6-43152061; COSMIC: COSV52730494; COSMIC: COSV52730494;