rs10498163

chr2-224569728-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000409096.5(CUL3):c.-46T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 1,209,746 control chromosomes in the GnomAD database, including 57,538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6533 hom., cov: 31)
  • Exomes 𝑓: 0.31 (51005 hom.)
• Consequence: CUL3 ENST00000409096.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.835

Genes affected

CUL3 (HGNC:2553): (cullin 3) This gene encodes a member of the cullin protein family. The encoded protein plays a critical role in the polyubiquitination and subsequent degradation of specific protein substrates as the core component and scaffold protein of an E3 ubiquitin ligase complex. Complexes including the encoded protein may also play a role in late endosome maturation. Mutations in this gene are a cause of type 2E pseudohypoaldosteronism. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-224569728-A-G is Benign according to our data. Variant chr2-224569728-A-G is described in ClinVar as [Benign]. Clinvar id is 504910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.329 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUL3	NM_003590.5	c.67-11872T>C		intron_variant		ENST00000264414.9
CUL3	NM_001257198.2	c.45T>C	p.His15=	synonymous_variant	1/16
CUL3	NM_001257197.2	c.66+15216T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUL3	ENST00000409096.5	c.-46T>C		5_prime_UTR_variant	1/16	1
CUL3	ENST00000264414.9	c.67-11872T>C		intron_variant		1	NM_003590.5	P1
CUL3	ENST00000344951.8	c.66+15216T>C		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43503 AN: 151772 Hom.: 6535 Cov.: 31

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.436

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.373

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.301

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.291

GnomAD3 exomes AF: 0.273 AC: 23123 AN: 84628 Hom.: 3365 AF XY: 0.272 AC XY: 13045 AN XY: 47964

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.299

Gnomad ASJ exome AF: 0.342

Gnomad EAS exome AF: 0.229

Gnomad SAS exome AF: 0.225

Gnomad FIN exome AF: 0.270

Gnomad NFE exome AF: 0.290

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.306 AC: 324205 AN: 1057856 Hom.: 51005 Cov.: 20 AF XY: 0.306 AC XY: 158532 AN XY: 518568

Gnomad4 AFR exome AF: 0.161

Gnomad4 AMR exome AF: 0.303

Gnomad4 ASJ exome AF: 0.361

Gnomad4 EAS exome AF: 0.278

Gnomad4 SAS exome AF: 0.244

Gnomad4 FIN exome AF: 0.279

Gnomad4 NFE exome AF: 0.314

Gnomad4 OTH exome AF: 0.306

GnomAD4 genome AF: 0.286 AC: 43504 AN: 151890 Hom.: 6533 Cov.: 31 AF XY: 0.287 AC XY: 21340 AN XY: 74242

Gnomad4 AFR AF: 0.177

Gnomad4 AMR AF: 0.333

Gnomad4 ASJ AF: 0.373

Gnomad4 EAS AF: 0.323

Gnomad4 SAS AF: 0.262

Gnomad4 FIN AF: 0.301

Gnomad4 NFE AF: 0.332

Gnomad4 OTH AF: 0.289

Alfa AF: 0.322 Hom.: 4410

Bravo AF: 0.286

Asia WGS AF: 0.284 AC: 991 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 21, 2016

p.His15His in exon 1 of CUL3: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 37.34% (1236/3310) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs10498163). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 11, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	7.8
Dann	Benign	0.65

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: rs10498163; hg19: chr2-225434445; COSMIC: COSV52361378;