10-35016247-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003591.4(CUL2):c.1832C>T(p.Thr611Ile) 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. 13/21 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: 5.92

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2884001).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUL2	NM_003591.4	c.1832C>T	p.Thr611Ile	missense_variant	18/21	ENST00000374749.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUL2	ENST00000374749.8	c.1832C>T	p.Thr611Ile	missense_variant	18/21	1	NM_003591.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Jan 26, 2022

The c.1889C>T (p.T630I) alteration is located in exon 18 (coding exon 18) of the CUL2 gene. This alteration results from a C to T substitution at nucleotide position 1889, causing the threonine (T) at amino acid position 630 to be replaced by an isoleucine (I). 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	0.086
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Benign	-0.079
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.29	T;T;T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	0.99	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.2	N;N;N;N;.;.;.
REVEL	Benign	0.19
Sift	Benign	0.21	T;T;T;T;.;.;.
Sift4G	Benign	0.19	T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;.;B;.
Vest4		0.44
MutPred		0.44		Loss of ubiquitination at K615 (P = 0.0391);Loss of ubiquitination at K615 (P = 0.0391);Loss of ubiquitination at K615 (P = 0.0391);Loss of ubiquitination at K615 (P = 0.0391);.;Loss of ubiquitination at K615 (P = 0.0391);.;
MVP		0.44
MPC		0.86
ClinPred		0.87	D
GERP RS		5.7
Varity_R		0.17
gMVP		0.22

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-35305175;