10-35044860-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003591.4(CUL2):c.515G>T(p.Gly172Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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: 6.08

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19243568).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUL2	NM_003591.4	c.515G>T	p.Gly172Val	missense_variant	7/21	ENST00000374749.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUL2	ENST00000374749.8	c.515G>T	p.Gly172Val	missense_variant	7/21	1	NM_003591.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Aug 10, 2023

The c.572G>T (p.G191V) alteration is located in exon 7 (coding exon 7) of the CUL2 gene. This alteration results from a G to T substitution at nucleotide position 572, causing the glycine (G) at amino acid position 191 to be replaced by a valine (V). 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	Benign	0.089
BayesDel_addAF	Benign	-0.0043	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	22
Dann	Benign	0.97
Eigen	Benign	-0.076
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.19	T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.37	N;N;N;N;.;.;.
REVEL	Benign	0.19
Sift	Benign	0.42	T;T;T;T;.;.;.
Sift4G	Benign	0.29	T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;.;B;.
Vest4		0.31
MutPred		0.54		Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);Loss of disorder (P = 0.0411);.;Loss of disorder (P = 0.0411);.;
MVP		0.36
MPC		1.0
ClinPred		0.79	D
GERP RS		5.9
Varity_R		0.28
gMVP		0.30

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: rs2085894147; hg19: chr10-35333788;