rs2396092

Variant names:

• chr2-224470573-A-G
• rs2396092
• NM_003590.5:c.*3672T>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.*3672T>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 0.177 in 231,390 control chromosomes in the GnomAD database, including 4,155 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2921 hom., cov: 33)
  • Exomes 𝑓: 0.16 (1234 hom.)
• Consequence: CUL3 NM_003590.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.336
• Publications: 10 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=-0.88).
• BP6: Variant 2-224470573-A-G is Benign according to our data. Variant chr2-224470573-A-G is described in ClinVar as Benign. ClinVar VariationId is 334575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.258 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.*3672T>C		3_prime_UTR	Exon 16 of 16	NP_003581.1	Q13618-1
	CUL3	NM_001257198.2		c.*3672T>C		3_prime_UTR	Exon 16 of 16	NP_001244127.1
	CUL3	NM_001257197.2		c.*3672T>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.*3672T>C		3_prime_UTR	Exon 16 of 16	ENSP00000264414.4	Q13618-1
	CUL3	ENST00000344951.8	TSL:2	c.*3672T>C		3_prime_UTR	Exon 15 of 15	ENSP00000343601.4	Q13618-3
	ENSG00000274629	ENST00000620050.1	TSL:5	n.242-3408A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27981 AN: 152026 Hom.: 2910 Cov.: 33

Gnomad AFR AF: 0.259

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.270

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.182

GnomAD4 exome AF: 0.163 AC: 12934 AN: 79246 Hom.: 1234 Cov.: 0 AF XY: 0.163 AC XY: 5946 AN XY: 36450

African (AFR) AF: 0.233 AC: 884 AN: 3802

American (AMR) AF: 0.212 AC: 519 AN: 2452

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 585 AN: 5044

East Asian (EAS) AF: 0.302 AC: 3335 AN: 11060

South Asian (SAS) AF: 0.263 AC: 179 AN: 680

European-Finnish (FIN) AF: 0.0517 AC: 3 AN: 58

Middle Eastern (MID) AF: 0.137 AC: 65 AN: 474

European-Non Finnish (NFE) AF: 0.129 AC: 6349 AN: 49054

Other (OTH) AF: 0.153 AC: 1015 AN: 6622

GnomAD4 genome AF: 0.184 AC: 28024 AN: 152144 Hom.: 2921 Cov.: 33 AF XY: 0.188 AC XY: 13951 AN XY: 74372

African (AFR) AF: 0.259 AC: 10756 AN: 41478

American (AMR) AF: 0.215 AC: 3285 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 377 AN: 3470

East Asian (EAS) AF: 0.266 AC: 1375 AN: 5170

South Asian (SAS) AF: 0.270 AC: 1302 AN: 4822

European-Finnish (FIN) AF: 0.150 AC: 1586 AN: 10602

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.129 AC: 8803 AN: 68002

Other (OTH) AF: 0.179 AC: 377 AN: 2110

Alfa AF: 0.153 Hom.: 5257

Bravo AF: 0.190

Asia WGS AF: 0.276 AC: 958 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	-0.88
CADD	Benign	2.5
DANN	Benign	0.52
PhyloP100		0.34
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: rs2396092; hg19: chr2-225335290;