rs4234054

Variant names:

• chr2-224470456-G-A
• rs4234054
• NM_003590.5:c.*3789C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-224470456-G-A
• chr2-224470456-G-C
• chr2-224470456-G-T

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.*3789C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.994 in 230,708 control chromosomes in the GnomAD database, including 114,034 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (75304 hom., cov: 32)
  • Exomes 𝑓: 0.99 (38730 hom.)
• Consequence: CUL3 NM_003590.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.170
• Publications: 3 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=-0.83).
• BP6: Variant 2-224470456-G-A is Benign according to our data. Variant chr2-224470456-G-A is described in ClinVar as Benign. ClinVar VariationId is 334570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.99 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.*3789C>T		3_prime_UTR	Exon 16 of 16	NP_003581.1	Q13618-1
	CUL3	NM_001257198.2		c.*3789C>T		3_prime_UTR	Exon 16 of 16	NP_001244127.1
	CUL3	NM_001257197.2		c.*3789C>T		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.*3789C>T		3_prime_UTR	Exon 16 of 16	ENSP00000264414.4	Q13618-1
	CUL3	ENST00000344951.8	TSL:2	c.*3789C>T		3_prime_UTR	Exon 15 of 15	ENSP00000343601.4	Q13618-3
	ENSG00000274629	ENST00000620050.1	TSL:5	n.242-3525G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.994 AC: 151343 AN: 152206 Hom.: 75246 Cov.: 32

Gnomad AFR AF: 0.998

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.992

Gnomad ASJ AF: 0.983

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 0.985

Gnomad MID AF: 1.00

Gnomad NFE AF: 0.994

Gnomad OTH AF: 0.994

GnomAD4 exome AF: 0.994 AC: 77919 AN: 78384 Hom.: 38730 Cov.: 0 AF XY: 0.993 AC XY: 35803 AN XY: 36040

African (AFR) AF: 0.998 AC: 3739 AN: 3746

American (AMR) AF: 0.991 AC: 2413 AN: 2434

Ashkenazi Jewish (ASJ) AF: 0.983 AC: 4865 AN: 4950

East Asian (EAS) AF: 1.00 AC: 10982 AN: 10982

South Asian (SAS) AF: 1.00 AC: 680 AN: 680

European-Finnish (FIN) AF: 1.00 AC: 56 AN: 56

Middle Eastern (MID) AF: 0.998 AC: 473 AN: 474

European-Non Finnish (NFE) AF: 0.994 AC: 48194 AN: 48508

Other (OTH) AF: 0.994 AC: 6517 AN: 6554

GnomAD4 genome AF: 0.994 AC: 151460 AN: 152324 Hom.: 75304 Cov.: 32 AF XY: 0.994 AC XY: 74037 AN XY: 74486

African (AFR) AF: 0.998 AC: 41492 AN: 41564

American (AMR) AF: 0.992 AC: 15184 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.983 AC: 3412 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5190 AN: 5190

South Asian (SAS) AF: 0.999 AC: 4825 AN: 4830

European-Finnish (FIN) AF: 0.985 AC: 10458 AN: 10614

Middle Eastern (MID) AF: 1.00 AC: 294 AN: 294

European-Non Finnish (NFE) AF: 0.994 AC: 67593 AN: 68032

Other (OTH) AF: 0.994 AC: 2101 AN: 2114

Alfa AF: 0.995 Hom.: 9496

Bravo AF: 0.995

Asia WGS AF: 0.999 AC: 3473 AN: 3478

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	-0.83
CADD	Benign	0.79
DANN	Benign	0.75
PhyloP100		0.17
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: rs4234054; hg19: chr2-225335173;