10-35038937-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003591.4(CUL2):c.860G>A(p.Arg287Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,433,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: CUL2 NM_003591.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.16

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18321875).
• BS2: High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUL2	NM_003591.4	c.860G>A	p.Arg287Gln	missense_variant	9/21	ENST00000374749.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUL2	ENST00000374749.8	c.860G>A	p.Arg287Gln	missense_variant	9/21	1	NM_003591.4	P3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000227 AC: 5 AN: 220632 Hom.: 0 AF XY: 0.0000336 AC XY: 4 AN XY: 118896

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000699

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000586

Gnomad SAS exome AF: 0.0000402

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000184

GnomAD4 exome AF: 0.0000112 AC: 16 AN: 1433300 Hom.: 0 Cov.: 29 AF XY: 0.0000112 AC XY: 8 AN XY: 711848

Gnomad4 AFR exome AF: 0.0000311

Gnomad4 AMR exome AF: 0.000154

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000248

Gnomad4 FIN exome AF: 0.0000190

Gnomad4 NFE exome AF: 0.00000455

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Dec 03, 2021

The c.917G>A (p.R306Q) alteration is located in exon 9 (coding exon 9) of the CUL2 gene. This alteration results from a G to A substitution at nucleotide position 917, causing the arginine (R) at amino acid position 306 to be replaced by a glutamine (Q). 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	0.073
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	23
Dann	Uncertain	0.99
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.18	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.90	N;N;N;N;.;.;.
REVEL	Benign	0.076
Sift	Benign	0.30	T;T;T;T;.;.;.
Sift4G	Benign	0.57	T;T;T;T;T;T;T
Polyphen		0.046	B;B;B;B;.;B;.
Vest4		0.53
MutPred		0.43		Gain of methylation at K290 (P = 0.0749);Gain of methylation at K290 (P = 0.0749);Gain of methylation at K290 (P = 0.0749);Gain of methylation at K290 (P = 0.0749);.;Gain of methylation at K290 (P = 0.0749);.;
MVP		0.42
MPC		0.92
ClinPred		0.19	T
GERP RS		2.2
Varity_R		0.16
gMVP		0.27

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

Publications

LitVar

Other links and lift over

dbSNP: rs1375537047; hg19: chr10-35327865; COSMIC: COSV66079394;