chr2-224569728-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001257198.2(CUL3):c.45T>C(p.His15His) variant causes a synonymous 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
NM_001257198.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.835

Variant links:

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]

CUL3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
CUL3	NM_003590.5 link	c.67-11872T>C		intron_variant	Intron 1 of 15	ENST00000264414.9	NP_003581.1	Q13618-1A0A024R475
CUL3	NM_001257198.2 link	c.45T>C	p.His15His	synonymous_variant	Exon 1 of 16		NP_001244127.1	Q13618
CUL3	NM_001257197.2 link	c.66+15216T>C		intron_variant	Intron 1 of 14		NP_001244126.1	Q13618-3B7Z600

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CUL3	ENST00000409096.5 link	c.-46T>C	5_prime_UTR_variant	Exon 1 of 16	1		ENSP00000387200.1	Q13618-2
CUL3	ENST00000264414.9 link	c.67-11872T>C	intron_variant	Intron 1 of 15	1	NM_003590.5	ENSP00000264414.4	Q13618-1
CUL3	ENST00000344951.8 link	c.66+15216T>C	intron_variant	Intron 1 of 14	2		ENSP00000343601.4	Q13618-3

Frequencies

GnomAD3 genomes

AF:

0.287

AC:

43503

AN:

151772

Hom.:

6535

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.306

AC XY:

158532

AN XY:

518568

show subpopulations

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.:

AF XY:

0.287

AC XY:

21340

AN XY:

74242

show subpopulations

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:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over