10-35016346-G-T

Variant names:

• chr10-35016346-G-T
• NM_003591.4:c.1733C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003591.4(CUL2):​c.1733C>A​(p.Thr578Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: CUL2 NM_003591.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.99
• Publications: 0 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL2	NM_003591.4	c.1733C>A	p.Thr578Lys	missense_variant	Exon 18 of 21	ENST00000374749.8	NP_003582.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL2	ENST00000374749.8	c.1733C>A	p.Thr578Lys	missense_variant	Exon 18 of 21	1	NM_003591.4	ENSP00000363881.3

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

Oct 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1790C>A (p.T597K) alteration is located in exon 18 (coding exon 18) of the CUL2 gene. This alteration results from a C to A substitution at nucleotide position 1790, causing the threonine (T) at amino acid position 597 to be replaced by a lysine (K). 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	0.96
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.62	.;D;D;D;.;.;.
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;.;.;D;D;D;D
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.090	T
MutationAssessor	Benign	1.5	.;L;L;L;.;.;.
PhyloP100		10
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.4	N;N;N;N;.;.;.
REVEL	Uncertain	0.62
Sift	Benign	0.28	T;T;T;T;.;.;.
Sift4G	Benign	0.12	T;T;T;T;T;T;T
Polyphen		0.69	P;P;P;P;.;P;.
Vest4		0.84
MutPred		0.86		Gain of methylation at T578 (P = 0.0073);Gain of methylation at T578 (P = 0.0073);Gain of methylation at T578 (P = 0.0073);Gain of methylation at T578 (P = 0.0073);.;Gain of methylation at T578 (P = 0.0073);.;
MVP		0.94
MPC		2.0
ClinPred		0.88	D
GERP RS		4.8
Varity_R		0.58
gMVP		0.91
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

hg19: chr10-35305274;