2-224481929-T-C

Variant names:

• chr2-224481929-T-C
• rs2070127
• NM_003590.5:c.1992A>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003590.5(CUL3):​c.1992A>G​(p.Gln664Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,588,794 control chromosomes in the GnomAD database, including 20,901 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2932 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17969 hom.)
• Consequence: CUL3 NM_003590.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.82

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-224481929-T-C is Benign according to our data. Variant chr2-224481929-T-C is described in ClinVar as [Benign]. Clinvar id is 259092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.82 with no splicing effect.
• 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.1992A>G	p.Gln664Gln	synonymous_variant	Exon 14 of 16	ENST00000264414.9	NP_003581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL3	ENST00000264414.9	c.1992A>G	p.Gln664Gln	synonymous_variant	Exon 14 of 16	1	NM_003590.5	ENSP00000264414.4

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28047 AN: 151926 Hom.: 2922 Cov.: 32

Gnomad AFR AF: 0.259

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.271

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.185

GnomAD3 exomes AF: 0.184 AC: 43668 AN: 237076 Hom.: 4656 AF XY: 0.182 AC XY: 23453 AN XY: 128568

Gnomad AFR exome AF: 0.262

Gnomad AMR exome AF: 0.246

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.274

Gnomad SAS exome AF: 0.266

Gnomad FIN exome AF: 0.158

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.169

GnomAD4 exome AF: 0.149 AC: 214367 AN: 1436750 Hom.: 17969 Cov.: 30 AF XY: 0.151 AC XY: 108058 AN XY: 713414

Gnomad4 AFR exome AF: 0.255

Gnomad4 AMR exome AF: 0.237

Gnomad4 ASJ exome AF: 0.112

Gnomad4 EAS exome AF: 0.292

Gnomad4 SAS exome AF: 0.256

Gnomad4 FIN exome AF: 0.160

Gnomad4 NFE exome AF: 0.130

Gnomad4 OTH exome AF: 0.163

GnomAD4 genome AF: 0.185 AC: 28090 AN: 152044 Hom.: 2932 Cov.: 32 AF XY: 0.188 AC XY: 13994 AN XY: 74302

Gnomad4 AFR AF: 0.260

Gnomad4 AMR AF: 0.216

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.268

Gnomad4 SAS AF: 0.271

Gnomad4 FIN AF: 0.150

Gnomad4 NFE AF: 0.130

Gnomad4 OTH AF: 0.182

Alfa AF: 0.142 Hom.: 1971

Bravo AF: 0.191

Asia WGS AF: 0.275 AC: 954 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 13, 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	-0.53
CADD	Benign	8.3
DANN	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2070127; hg19: chr2-225346646; COSMIC: COSV52361484; COSMIC: COSV52361484;