2-224502952-C-T

Variant names:

• chr2-224502952-C-T
• rs3754629
• NM_003590.5:c.1485+13G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003590.5(CUL3):​c.1485+13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.154 in 1,578,040 control chromosomes in the GnomAD database, including 21,159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (2951 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18208 hom.)
• Consequence: CUL3 NM_003590.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.817
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder with or without autism or seizures

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• pseudohypoaldosteronism type 2E

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-224502952-C-T is Benign according to our data. Variant chr2-224502952-C-T is described in ClinVar as Benign. ClinVar VariationId is 259090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL3	NM_003590.5	c.1485+13G>A		intron_variant	Intron 10 of 15	ENST00000264414.9	NP_003581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL3	ENST00000264414.9	c.1485+13G>A		intron_variant	Intron 10 of 15	1	NM_003590.5	ENSP00000264414.4

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28180 AN: 151936 Hom.: 2940 Cov.: 32

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.266

Gnomad SAS AF: 0.271

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.185

GnomAD2 exomes AF: 0.185 AC: 46189 AN: 249288 AF XY: 0.184

Gnomad AFR exome AF: 0.262

Gnomad AMR exome AF: 0.240

Gnomad ASJ exome AF: 0.116

Gnomad EAS exome AF: 0.271

Gnomad FIN exome AF: 0.165

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.172

GnomAD4 exome AF: 0.151 AC: 215250 AN: 1425988 Hom.: 18208 Cov.: 26 AF XY: 0.153 AC XY: 109003 AN XY: 711402

African (AFR) AF: 0.255 AC: 8356 AN: 32744

American (AMR) AF: 0.234 AC: 10347 AN: 44184

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 2990 AN: 25844

East Asian (EAS) AF: 0.290 AC: 11444 AN: 39460

South Asian (SAS) AF: 0.255 AC: 21664 AN: 84906

European-Finnish (FIN) AF: 0.167 AC: 8888 AN: 53340

Middle Eastern (MID) AF: 0.139 AC: 791 AN: 5708

European-Non Finnish (NFE) AF: 0.130 AC: 141008 AN: 1080550

Other (OTH) AF: 0.165 AC: 9762 AN: 59252

GnomAD4 genome AF: 0.186 AC: 28224 AN: 152052 Hom.: 2951 Cov.: 32 AF XY: 0.189 AC XY: 14072 AN XY: 74324

African (AFR) AF: 0.261 AC: 10804 AN: 41460

American (AMR) AF: 0.216 AC: 3295 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 394 AN: 3464

East Asian (EAS) AF: 0.267 AC: 1378 AN: 5166

South Asian (SAS) AF: 0.271 AC: 1303 AN: 4814

European-Finnish (FIN) AF: 0.156 AC: 1655 AN: 10590

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.130 AC: 8849 AN: 67970

Other (OTH) AF: 0.183 AC: 386 AN: 2114

Alfa AF: 0.149 Hom.: 610

Bravo AF: 0.191

Asia WGS AF: 0.274 AC: 952 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 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

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant pseudohypoaldosteronism type 1 Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Pseudohypoaldosteronism type 2E Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	10
DANN	Benign	0.65
PhyloP100		-0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3754629; hg19: chr2-225367669; COSMIC: COSV52365070; COSMIC: COSV52365070;