rs886055679

Variant names:

• chr2-224470479-C-T
• rs886055679
• NM_003590.5:c.*3766G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_003590.5(CUL3):​c.*3766G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000261 in 229,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: CUL3 NM_003590.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.511
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae)
• pseudohypoaldosteronism type 2E

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

ENSG00000274629 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003590.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL3	NM_003590.5	MANE Select	c.*3766G>A		3_prime_UTR	Exon 16 of 16	NP_003581.1	Q13618-1
	CUL3	NM_001257198.2		c.*3766G>A		3_prime_UTR	Exon 16 of 16	NP_001244127.1
	CUL3	NM_001257197.2		c.*3766G>A		3_prime_UTR	Exon 15 of 15	NP_001244126.1	Q13618-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL3	ENST00000264414.9	TSL:1 MANE Select	c.*3766G>A		3_prime_UTR	Exon 16 of 16	ENSP00000264414.4	Q13618-1
	CUL3	ENST00000344951.8	TSL:2	c.*3766G>A		3_prime_UTR	Exon 15 of 15	ENSP00000343601.4	Q13618-3
	ENSG00000274629	ENST00000620050.1	TSL:5	n.242-3502C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151314 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000383 AC: 3 AN: 78364 Hom.: 0 Cov.: 0 AF XY: 0.0000555 AC XY: 2 AN XY: 36036

African (AFR) AF: 0.00 AC: 0 AN: 3742

American (AMR) AF: 0.000414 AC: 1 AN: 2416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4966

East Asian (EAS) AF: 0.00 AC: 0 AN: 10960

South Asian (SAS) AF: 0.00 AC: 0 AN: 684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 58

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 470

European-Non Finnish (NFE) AF: 0.0000412 AC: 2 AN: 48550

Other (OTH) AF: 0.00 AC: 0 AN: 6518

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151314 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 73852

African (AFR) AF: 0.00 AC: 0 AN: 41000

American (AMR) AF: 0.00 AC: 0 AN: 15102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00 AC: 0 AN: 4750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67978

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal dominant pseudohypoaldosteronism type 1 (1)
-	1	-	Pseudohypoaldosteronism type 2E (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.5
DANN	Benign	0.77
PhyloP100		-0.51

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

Other links and lift over

dbSNP: rs886055679; hg19: chr2-225335196;