NM_003591.4:c.2216A>G

Variant names:

• chr10-35010333-T-C
• rs964032175
• NM_003591.4:c.2216A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003591.4(CUL2):​c.2216A>G​(p.Asp739Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,390 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CUL2 NM_003591.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.01
• Publications: 1 publications found

Genes affected

CUL2 (HGNC:2552): (cullin 2) 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 protein catabolic process. Located in nucleoplasm. Part of Cul2-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000301061 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003591.4. 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
	CUL2	NM_003591.4	MANE Select	c.2216A>G	p.Asp739Gly	missense	Exon 21 of 21	NP_003582.2
	CUL2	NM_001198778.2		c.2273A>G	p.Asp758Gly	missense	Exon 21 of 21	NP_001185707.1	Q13617-2
	CUL2	NM_001198779.1		c.2255A>G	p.Asp752Gly	missense	Exon 21 of 21	NP_001185708.1	Q13617

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL2	ENST00000374749.8	TSL:1 MANE Select	c.2216A>G	p.Asp739Gly	missense	Exon 21 of 21	ENSP00000363881.3	Q13617-1
	CUL2	ENST00000374751.7	TSL:1	c.2216A>G	p.Asp739Gly	missense	Exon 21 of 21	ENSP00000363883.3	Q13617-1
	CUL2	ENST00000970364.1		c.2282A>G	p.Asp761Gly	missense	Exon 22 of 22	ENSP00000640423.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458390 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725554

African (AFR) AF: 0.00 AC: 0 AN: 33202

American (AMR) AF: 0.00 AC: 0 AN: 44182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39420

South Asian (SAS) AF: 0.00 AC: 0 AN: 85740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

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

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110456

Other (OTH) AF: 0.00 AC: 0 AN: 60238

GnomAD4 genome Cov.: 32

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	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		8.0
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.49		Loss of stability (P = 0.0643)
MVP		0.88
MPC		2.2
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.83
gMVP		0.69
Mutation Taster		=9/91	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: rs964032175; hg19: chr10-35299261;