chr10-35044781-G-C

Position:

• chr10-35044781-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003591.4(CUL2):​c.594C>G​(p.Phe198Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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: 2.10

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10757944).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUL2	NM_003591.4	c.594C>G	p.Phe198Leu	missense_variant	7/21	ENST00000374749.8	NP_003582.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL2	ENST00000374749.8	c.594C>G	p.Phe198Leu	missense_variant	7/21	1	NM_003591.4	ENSP00000363881	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Mar 30, 2024

The c.651C>G (p.F217L) alteration is located in exon 7 (coding exon 7) of the CUL2 gene. This alteration results from a C to G substitution at nucleotide position 651, causing the phenylalanine (F) at amino acid position 217 to be replaced by a leucine (L). 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	0.59
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Benign	0.37	.;T;T;T;.;.;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	.;.;.;D;D;D;D
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	.;N;N;N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.60	N;N;N;N;.;.;.
REVEL	Benign	0.096
Sift	Benign	0.66	T;T;T;T;.;.;.
Sift4G	Benign	0.79	T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;.;B;.
Vest4		0.33
MutPred		0.41		Loss of methylation at K197 (P = 0.0318);Loss of methylation at K197 (P = 0.0318);Loss of methylation at K197 (P = 0.0318);Loss of methylation at K197 (P = 0.0318);.;Loss of methylation at K197 (P = 0.0318);.;
MVP		0.33
MPC		0.99
ClinPred		0.12	T
GERP RS		1.4
Varity_R		0.10
gMVP		0.45

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: chr10-35333709;