10-35049676-C-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003591.4(CUL2):c.506+7G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00807 in 1,607,258 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0065 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (85 hom.)
• Consequence: CUL2 NM_003591.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006623
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.00

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 10-35049676-C-G is Benign according to our data. Variant chr10-35049676-C-G is described in ClinVar as [Benign]. Clinvar id is 708941.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 996 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUL2	NM_003591.4	c.506+7G>C		splice_region_variant, intron_variant		ENST00000374749.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUL2	ENST00000374749.8	c.506+7G>C		splice_region_variant, intron_variant		1	NM_003591.4	P3

Frequencies

GnomAD3 genomes AF: 0.00655 AC: 996 AN: 152096 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0343

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00798

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00691 AC: 1724 AN: 249468 Hom.: 12 AF XY: 0.00677 AC XY: 912 AN XY: 134794

Gnomad AFR exome AF: 0.00170

Gnomad AMR exome AF: 0.00134

Gnomad ASJ exome AF: 0.00271

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000992

Gnomad FIN exome AF: 0.0329

Gnomad NFE exome AF: 0.00754

Gnomad OTH exome AF: 0.00951

GnomAD4 exome AF: 0.00823 AC: 11979 AN: 1455044 Hom.: 85 Cov.: 29 AF XY: 0.00803 AC XY: 5812 AN XY: 724098

Gnomad4 AFR exome AF: 0.00135

Gnomad4 AMR exome AF: 0.00155

Gnomad4 ASJ exome AF: 0.00246

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000175

Gnomad4 FIN exome AF: 0.0330

Gnomad4 NFE exome AF: 0.00871

Gnomad4 OTH exome AF: 0.00640

GnomAD4 genome AF: 0.00654 AC: 996 AN: 152214 Hom.: 8 Cov.: 32 AF XY: 0.00738 AC XY: 549 AN XY: 74386

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0343

Gnomad4 NFE AF: 0.00798

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00706 Hom.: 2

Bravo AF: 0.00427

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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

Apr 10, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	1.2
Dann	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000066
dbscSNV1_RF	Benign	0.0
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

LitVar

Other links and lift over

dbSNP: rs145366778; hg19: chr10-35338604;