6-43184546-T-C

Variant names:

• chr6-43184546-T-C
• rs762906906
• NM_015089.4:c.236T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_015089.4(CUL9):​c.236T>C​(p.Leu79Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,612,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L79L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CUL9 NM_015089.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.75
• Publications: 0 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL9	NM_015089.4	c.236T>C	p.Leu79Pro	missense_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.236T>C	p.Leu79Pro	missense_variant	Exon 2 of 41	5	NM_015089.4	ENSP00000252050.4
CUL9	ENST00000372647.6	c.236T>C	p.Leu79Pro	missense_variant	Exon 2 of 41	1		ENSP00000361730.2
CUL9	ENST00000451399.5	n.311T>C		non_coding_transcript_exon_variant	Exon 2 of 5	2
CUL9	ENST00000515773.5	n.311T>C		non_coding_transcript_exon_variant	Exon 2 of 40	2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152190 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: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251230 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460622 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 726292

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111052

Other (OTH) AF: 0.00 AC: 0 AN: 60330

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.236T>C (p.L79P) alteration is located in exon 2 (coding exon 1) of the CUL9 gene. This alteration results from a T to C substitution at nucleotide position 236, causing the leucine (L) at amino acid position 79 to be replaced by a proline (P). 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	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.9	M;.
PhyloP100		7.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.79
MutPred		0.69		Gain of loop (P = 0.0079);Gain of loop (P = 0.0079);
MVP		0.84
MPC		1.4
ClinPred		0.88	D
GERP RS		4.0
Varity_R		0.93
gMVP		0.93
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs762906906; hg19: chr6-43152284;