10-35011943-C-T

Variant names:

• chr10-35011943-C-T
• rs762500449
• NM_003591.4:c.2011G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003591.4(CUL2):​c.2011G>A​(p.Ala671Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A671S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CUL2 NM_003591.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.90
• 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 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.2011G>A	p.Ala671Thr	missense_variant	Exon 20 of 21	ENST00000374749.8	NP_003582.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL2	ENST00000374749.8	c.2011G>A	p.Ala671Thr	missense_variant	Exon 20 of 21	1	NM_003591.4	ENSP00000363881.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Benign	0.71
DEOGEN2	Benign	0.26	T;T;T;.;.
Eigen	Benign	0.071
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;.;D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.53	D;D;D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-0.67	N;N;N;.;.
PhyloP100		7.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.59	N;N;N;.;.
REVEL	Benign	0.27
Sift	Benign	0.62	T;T;T;.;.
Sift4G	Benign	0.72	T;T;T;T;T
Polyphen		0.40	B;B;B;.;.
Vest4		0.86
MutPred		0.29		Gain of phosphorylation at A671 (P = 0.0065);Gain of phosphorylation at A671 (P = 0.0065);Gain of phosphorylation at A671 (P = 0.0065);.;.;
MVP		0.83
MPC		1.9
ClinPred		0.84	D
GERP RS		6.2
Varity_R		0.31
gMVP		0.25
Mutation Taster		=18/82	disease causing

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

Other links and lift over

dbSNP: rs762500449; hg19: chr10-35300871;