rs12470077

Variant names:

• chr2-224470254-T-C
• rs12470077
• NM_003590.5:c.*3991A>G

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.*3991A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 218,334 control chromosomes in the GnomAD database, including 10,928 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7139 hom., cov: 32)
  • Exomes 𝑓: 0.33 (3789 hom.)
• Consequence: CUL3 NM_003590.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.305
• Publications: 8 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 2-224470254-T-C is Benign according to our data. Variant chr2-224470254-T-C is described in ClinVar as Benign. ClinVar VariationId is 334569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.366 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.*3991A>G		3_prime_UTR	Exon 16 of 16	NP_003581.1	Q13618-1
	CUL3	NM_001257198.2		c.*3991A>G		3_prime_UTR	Exon 16 of 16	NP_001244127.1
	CUL3	NM_001257197.2		c.*3991A>G		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.*3991A>G		3_prime_UTR	Exon 16 of 16	ENSP00000264414.4	Q13618-1
	CUL3	ENST00000344951.8	TSL:2	c.*3991A>G		3_prime_UTR	Exon 15 of 15	ENSP00000343601.4	Q13618-3
	ENSG00000274629	ENST00000620050.1	TSL:5	n.242-3727T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.301 AC: 45810 AN: 152030 Hom.: 7141 Cov.: 32

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.436

Gnomad AMR AF: 0.348

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.303

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.302

GnomAD4 exome AF: 0.333 AC: 22034 AN: 66186 Hom.: 3789 Cov.: 0 AF XY: 0.334 AC XY: 10239 AN XY: 30656

African (AFR) AF: 0.235 AC: 712 AN: 3024

American (AMR) AF: 0.355 AC: 699 AN: 1970

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 1627 AN: 4218

East Asian (EAS) AF: 0.359 AC: 3390 AN: 9434

South Asian (SAS) AF: 0.238 AC: 133 AN: 558

European-Finnish (FIN) AF: 0.261 AC: 12 AN: 46

Middle Eastern (MID) AF: 0.369 AC: 150 AN: 406

European-Non Finnish (NFE) AF: 0.329 AC: 13470 AN: 40986

Other (OTH) AF: 0.332 AC: 1841 AN: 5544

GnomAD4 genome AF: 0.301 AC: 45825 AN: 152148 Hom.: 7139 Cov.: 32 AF XY: 0.302 AC XY: 22460 AN XY: 74350

African (AFR) AF: 0.217 AC: 8997 AN: 41522

American (AMR) AF: 0.349 AC: 5330 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 1287 AN: 3466

East Asian (EAS) AF: 0.380 AC: 1968 AN: 5174

South Asian (SAS) AF: 0.265 AC: 1278 AN: 4822

European-Finnish (FIN) AF: 0.303 AC: 3206 AN: 10578

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.333 AC: 22605 AN: 67984

Other (OTH) AF: 0.300 AC: 635 AN: 2114

Alfa AF: 0.330 Hom.: 2891

Bravo AF: 0.303

Asia WGS AF: 0.319 AC: 1114 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	5.3
DANN	Benign	0.71
PhyloP100		-0.30
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: rs12470077; hg19: chr2-225334971;