NM_003590.5:c.*3367T>C

Variant names:

• chr2-224470878-A-G
• rs4674908
• NM_003590.5:c.*3367T>C

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.*3367T>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 0.497 in 229,088 control chromosomes in the GnomAD database, including 28,793 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18671 hom., cov: 33)
  • Exomes 𝑓: 0.51 (10122 hom.)
• Consequence: CUL3 NM_003590.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.980
• Publications: 11 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-224470878-A-G is Benign according to our data. Variant chr2-224470878-A-G is described in ClinVar as Benign. ClinVar VariationId is 334580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.628 is higher than 0.05.

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.*3367T>C		3_prime_UTR	Exon 16 of 16	NP_003581.1	Q13618-1
	CUL3	NM_001257198.2		c.*3367T>C		3_prime_UTR	Exon 16 of 16	NP_001244127.1
	CUL3	NM_001257197.2		c.*3367T>C		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.*3367T>C		3_prime_UTR	Exon 16 of 16	ENSP00000264414.4	Q13618-1
	CUL3	ENST00000344951.8	TSL:2	c.*3367T>C		3_prime_UTR	Exon 15 of 15	ENSP00000343601.4	Q13618-3
	ENSG00000274629	ENST00000620050.1	TSL:5	n.242-3103A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74831 AN: 151916 Hom.: 18647 Cov.: 33

Gnomad AFR AF: 0.481

Gnomad AMI AF: 0.572

Gnomad AMR AF: 0.574

Gnomad ASJ AF: 0.497

Gnomad EAS AF: 0.648

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.458

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.470

Gnomad OTH AF: 0.491

GnomAD4 exome AF: 0.507 AC: 39067 AN: 77054 Hom.: 10122 Cov.: 0 AF XY: 0.507 AC XY: 18037 AN XY: 35560

African (AFR) AF: 0.470 AC: 1726 AN: 3672

American (AMR) AF: 0.572 AC: 1369 AN: 2394

Ashkenazi Jewish (ASJ) AF: 0.517 AC: 2518 AN: 4872

East Asian (EAS) AF: 0.662 AC: 7158 AN: 10812

South Asian (SAS) AF: 0.518 AC: 344 AN: 664

European-Finnish (FIN) AF: 0.268 AC: 15 AN: 56

Middle Eastern (MID) AF: 0.526 AC: 246 AN: 468

European-Non Finnish (NFE) AF: 0.472 AC: 22476 AN: 47662

Other (OTH) AF: 0.498 AC: 3215 AN: 6454

GnomAD4 genome AF: 0.493 AC: 74897 AN: 152034 Hom.: 18671 Cov.: 33 AF XY: 0.497 AC XY: 36921 AN XY: 74310

African (AFR) AF: 0.482 AC: 19977 AN: 41472

American (AMR) AF: 0.575 AC: 8779 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.497 AC: 1724 AN: 3470

East Asian (EAS) AF: 0.646 AC: 3341 AN: 5168

South Asian (SAS) AF: 0.536 AC: 2583 AN: 4818

European-Finnish (FIN) AF: 0.458 AC: 4842 AN: 10580

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.470 AC: 31940 AN: 67930

Other (OTH) AF: 0.486 AC: 1026 AN: 2110

Alfa AF: 0.487 Hom.: 31769

Bravo AF: 0.501

Asia WGS AF: 0.599 AC: 2083 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal dominant pseudohypoaldosteronism type 1 (1)
-	-	1	not provided (1)
-	-	1	Pseudohypoaldosteronism type 2E (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.12
DANN	Benign	0.46
PhyloP100		-0.98
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

Other links and lift over

dbSNP: rs4674908; hg19: chr2-225335595;