10-35010318-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003591.4(CUL2):c.2231T>C(p.Val744Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CUL2 NM_003591.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.31

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUL2	NM_003591.4	c.2231T>C	p.Val744Ala	missense_variant	21/21	ENST00000374749.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUL2	ENST00000374749.8	c.2231T>C	p.Val744Ala	missense_variant	21/21	1	NM_003591.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

The c.2288T>C (p.V763A) alteration is located in exon 21 (coding exon 21) of the CUL2 gene. This alteration results from a T to C substitution at nucleotide position 2288, causing the valine (V) at amino acid position 763 to be replaced by an alanine (A). 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	0.84
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.16	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.2	D;D;D;D;.;.;.
REVEL	Uncertain	0.60
Sift	Uncertain	0.0040	D;D;D;D;.;.;.
Sift4G	Uncertain	0.010	D;D;D;D;D;D;D
Polyphen		0.67	.;P;P;P;.;.;.
Vest4		0.71
MutPred		0.36		.;Loss of stability (P = 0.0663);Loss of stability (P = 0.0663);Loss of stability (P = 0.0663);.;.;.;
MVP		0.87
MPC		2.1
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.54
gMVP		0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs2084867547; hg19: chr10-35299246;