10-35049745-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BA1

The NM_003591.4(CUL2):c.444G>A(p.Arg148=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00598 in 1,612,868 control chromosomes in the GnomAD database, including 445 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.030 (223 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (222 hom.)
• Consequence: CUL2 NM_003591.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.09

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 10-35049745-C-T is Benign according to our data. Variant chr10-35049745-C-T is described in ClinVar as [Benign]. Clinvar id is 776506.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.09 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUL2	NM_003591.4	c.444G>A	p.Arg148=	synonymous_variant	6/21	ENST00000374749.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUL2	ENST00000374749.8	c.444G>A	p.Arg148=	synonymous_variant	6/21	1	NM_003591.4	P3

Frequencies

GnomAD3 genomes AF: 0.0296 AC: 4504 AN: 152118 Hom.: 223 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00864

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00757 AC: 1888 AN: 249544 Hom.: 86 AF XY: 0.00533 AC XY: 719 AN XY: 134798

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.00433

Gnomad ASJ exome AF: 0.000403

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000199

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000460

Gnomad OTH exome AF: 0.00409

GnomAD4 exome AF: 0.00351 AC: 5124 AN: 1460632 Hom.: 222 Cov.: 30 AF XY: 0.00304 AC XY: 2211 AN XY: 726526

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.00497

Gnomad4 ASJ exome AF: 0.000538

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000314

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000575

Gnomad4 OTH exome AF: 0.00694

GnomAD4 genome AF: 0.0297 AC: 4514 AN: 152236 Hom.: 223 Cov.: 32 AF XY: 0.0289 AC XY: 2152 AN XY: 74462

Gnomad4 AFR AF: 0.103

Gnomad4 AMR AF: 0.00863

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0148 Hom.: 49

Bravo AF: 0.0333

Asia WGS AF: 0.00404 AC: 15 AN: 3478

EpiCase AF: 0.000710

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 08, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
Cadd	Benign	10
Dann	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7897024; hg19: chr10-35338673;