chr10-35029597-T-A

Variant names:

• chr10-35029597-T-A
• rs143479297
• NM_003591.4:c.1430A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003591.4(CUL2):​c.1430A>T​(p.Tyr477Phe) 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 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: 8.02
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31558993).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL2	NM_003591.4	c.1430A>T	p.Tyr477Phe	missense_variant	Exon 15 of 21	ENST00000374749.8	NP_003582.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL2	ENST00000374749.8	c.1430A>T	p.Tyr477Phe	missense_variant	Exon 15 of 21	1	NM_003591.4	ENSP00000363881.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1487A>T (p.Y496F) alteration is located in exon 15 (coding exon 15) of the CUL2 gene. This alteration results from a A to T substitution at nucleotide position 1487, causing the tyrosine (Y) at amino acid position 496 to be replaced by a phenylalanine (F). 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	0.11
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	20
DANN	Benign	0.32
DEOGEN2	Benign	0.37	.;T;T;T;.;.;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	.;.;.;D;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.32	T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.3	.;N;N;N;.;.;.
PhyloP100		8.0
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	0.97	N;N;N;N;.;.;.
REVEL	Uncertain	0.32
Sift	Benign	1.0	T;T;T;T;.;.;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.0030	B;B;B;B;.;B;.
Vest4		0.61
MVP		0.78
MPC		1.6
ClinPred		0.81	D
GERP RS		4.9
Varity_R		0.33
gMVP		0.40
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

dbSNP: rs143479297; hg19: chr10-35318525;