2-224471300-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003590.5(CUL3):​c.*2945G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00441 in 204,628 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0042 ( 2 hom., cov: 33)
Exomes 𝑓: 0.0051 ( 1 hom. )

Consequence

CUL3
NM_003590.5 3_prime_UTR

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.0330
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
Variant 2-224471300-C-G is Benign according to our data. Variant chr2-224471300-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 334586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00418 (636/152176) while in subpopulation NFE AF= 0.00677 (460/67982). AF 95% confidence interval is 0.00626. There are 2 homozygotes in gnomad4. There are 308 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 636 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CUL3NM_003590.5 linkuse as main transcriptc.*2945G>C 3_prime_UTR_variant 16/16 ENST00000264414.9 NP_003581.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CUL3ENST00000264414.9 linkuse as main transcriptc.*2945G>C 3_prime_UTR_variant 16/161 NM_003590.5 ENSP00000264414 P1Q13618-1
ENST00000620050.1 linkuse as main transcriptn.242-2681C>G intron_variant, non_coding_transcript_variant 5
CUL3ENST00000344951.8 linkuse as main transcriptc.*2945G>C 3_prime_UTR_variant 15/152 ENSP00000343601 Q13618-3
ENST00000622296.1 linkuse as main transcriptn.54-1627C>G intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
AF:
0.00419
AC:
637
AN:
152058
Hom.:
2
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00140
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00603
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00104
Gnomad FIN
AF:
0.000189
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00678
Gnomad OTH
AF:
0.00860
GnomAD4 exome
AF:
0.00509
AC:
267
AN:
52452
Hom.:
1
Cov.:
0
AF XY:
0.00510
AC XY:
124
AN XY:
24306
show subpopulations
Gnomad4 AFR exome
AF:
0.000424
Gnomad4 AMR exome
AF:
0.00584
Gnomad4 ASJ exome
AF:
0.000297
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00713
Gnomad4 OTH exome
AF:
0.00617
GnomAD4 genome
AF:
0.00418
AC:
636
AN:
152176
Hom.:
2
Cov.:
33
AF XY:
0.00414
AC XY:
308
AN XY:
74414
show subpopulations
Gnomad4 AFR
AF:
0.00140
Gnomad4 AMR
AF:
0.00602
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00104
Gnomad4 FIN
AF:
0.000189
Gnomad4 NFE
AF:
0.00677
Gnomad4 OTH
AF:
0.00851
Alfa
AF:
0.000694
Hom.:
0
Bravo
AF:
0.00459

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal dominant pseudohypoaldosteronism type 1 Benign:1
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenOct 01, 2022CUL3: BS1, BS2 -
Pseudohypoaldosteronism type 2E Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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
-0.82
CADD
Benign
1.6
DANN
Benign
0.64

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

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

Other links and lift over

dbSNP: rs41529948; hg19: chr2-225336017; API