2-224481929-T-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.82

Publications

22 publications found
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 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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
CUL3NM_003590.5 linkc.1992A>G p.Gln664Gln synonymous_variant Exon 14 of 16 ENST00000264414.9 NP_003581.1 Q13618-1A0A024R475

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CUL3ENST00000264414.9 linkc.1992A>G p.Gln664Gln synonymous_variant Exon 14 of 16 1 NM_003590.5 ENSP00000264414.4 Q13618-1

Frequencies

GnomAD3 genomes
AF:
0.185
AC:
28047
AN:
151926
Hom.:
2922
Cov.:
32
show subpopulations
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
GnomAD2 exomes
AF:
0.184
AC:
43668
AN:
237076
AF XY:
0.182
show subpopulations
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 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
show subpopulations
African (AFR)
AF:
0.255
AC:
8259
AN:
32450
American (AMR)
AF:
0.237
AC:
9819
AN:
41434
Ashkenazi Jewish (ASJ)
AF:
0.112
AC:
2903
AN:
25920
East Asian (EAS)
AF:
0.292
AC:
11275
AN:
38624
South Asian (SAS)
AF:
0.256
AC:
20378
AN:
79566
European-Finnish (FIN)
AF:
0.160
AC:
8497
AN:
53250
Middle Eastern (MID)
AF:
0.137
AC:
721
AN:
5256
European-Non Finnish (NFE)
AF:
0.130
AC:
142822
AN:
1100750
Other (OTH)
AF:
0.163
AC:
9693
AN:
59500
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.469
Heterozygous variant carriers
0
7322
14644
21966
29288
36610
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
5430
10860
16290
21720
27150
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.185
AC:
28090
AN:
152044
Hom.:
2932
Cov.:
32
AF XY:
0.188
AC XY:
13994
AN XY:
74302
show subpopulations
African (AFR)
AF:
0.260
AC:
10763
AN:
41472
American (AMR)
AF:
0.216
AC:
3295
AN:
15276
Ashkenazi Jewish (ASJ)
AF:
0.111
AC:
383
AN:
3466
East Asian (EAS)
AF:
0.268
AC:
1386
AN:
5176
South Asian (SAS)
AF:
0.271
AC:
1305
AN:
4822
European-Finnish (FIN)
AF:
0.150
AC:
1591
AN:
10590
Middle Eastern (MID)
AF:
0.129
AC:
38
AN:
294
European-Non Finnish (NFE)
AF:
0.130
AC:
8821
AN:
67928
Other (OTH)
AF:
0.182
AC:
384
AN:
2108
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
1142
2284
3426
4568
5710
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
300
600
900
1200
1500
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.144
Hom.:
2477
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
LINK: link

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 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
PhyloP100
1.8
Mutation Taster
=100/0
polymorphism (auto)

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

Other links and lift over

dbSNP: rs2070127; hg19: chr2-225346646; COSMIC: COSV52361484; COSMIC: COSV52361484; API