10-35031517-T-C

Variant names:

• chr10-35031517-T-C
• rs764958342
• NM_003591.4:c.1273A>G

Variant summary

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

The NM_003591.4(CUL2):​c.1273A>G​(p.Ile425Val) 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: 33)
• Consequence: CUL2 NM_003591.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.01

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 rank	MANE	Protein	UniProt
CUL2	NM_003591.4	c.1273A>G	p.Ile425Val	missense_variant	Exon 13 of 21	ENST00000374749.8	NP_003582.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL2	ENST00000374749.8	c.1273A>G	p.Ile425Val	missense_variant	Exon 13 of 21	1	NM_003591.4	ENSP00000363881.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251246 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135784

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1330A>G (p.I444V) alteration is located in exon 13 (coding exon 13) of the CUL2 gene. This alteration results from a A to G substitution at nucleotide position 1330, causing the isoleucine (I) at amino acid position 444 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	0.098
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	.;T;T;T;.;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;.;.;D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.51	D;D;D;D;D;D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.5	.;L;L;L;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.73	N;N;N;N;N;.;.
REVEL	Uncertain	0.34
Sift	Benign	0.20	T;T;T;T;D;.;.
Sift4G	Benign	0.29	T;T;T;T;T;T;T
Polyphen		0.58	P;P;P;P;.;P;.
Vest4		0.36
MutPred		0.84		Loss of ubiquitination at K423 (P = 0.0853);Loss of ubiquitination at K423 (P = 0.0853);Loss of ubiquitination at K423 (P = 0.0853);Loss of ubiquitination at K423 (P = 0.0853);.;Loss of ubiquitination at K423 (P = 0.0853);.;
MVP		0.81
MPC		0.83
ClinPred		0.53	D
GERP RS		5.9
Varity_R		0.13
gMVP		0.42

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: rs764958342; hg19: chr10-35320445;