10-35010427-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003591.4(CUL2):c.2122A>G(p.Arg708Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,457,654 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CUL2 NM_003591.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.20

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32683322).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUL2	NM_003591.4	c.2122A>G	p.Arg708Gly	missense_variant	21/21	ENST00000374749.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUL2	ENST00000374749.8	c.2122A>G	p.Arg708Gly	missense_variant	21/21	1	NM_003591.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457654 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725096

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000227

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000234

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Apr 12, 2022

The c.2179A>G (p.R727G) alteration is located in exon 21 (coding exon 21) of the CUL2 gene. This alteration results from a A to G substitution at nucleotide position 2179, causing the arginine (R) at amino acid position 727 to be replaced by a glycine (G). 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	Uncertain	0.56
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	22
Dann	Uncertain	0.98
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.037
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.6	D;D;D;D;.;.;.
REVEL	Uncertain	0.38
Sift	Benign	0.045	D;D;D;D;.;.;.
Sift4G	Benign	0.072	T;T;T;T;T;T;T
Polyphen		0.0010	.;B;B;B;.;.;.
Vest4		0.40
MutPred		0.60		.;Loss of MoRF binding (P = 0.0365);Loss of MoRF binding (P = 0.0365);Loss of MoRF binding (P = 0.0365);.;.;.;
MVP		0.78
MPC		1.1
ClinPred		0.88	D
GERP RS		3.3
Varity_R		0.62
gMVP		0.34

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: chr10-35299355;