rs748865811

Variant names:

• chr2-224471219-C-T
• rs748865811
• NM_003590.5:c.*3026G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_003590.5(CUL3):​c.*3026G>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 0.000318 in 210,920 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 0.00031 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: CUL3 NM_003590.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.491
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000309 (47/152110) while in subpopulation NFE AF = 0.000632 (43/68008). AF 95% confidence interval is 0.000482. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 47 AD gene.

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.*3026G>A		3_prime_UTR	Exon 16 of 16	NP_003581.1	Q13618-1
	CUL3	NM_001257198.2		c.*3026G>A		3_prime_UTR	Exon 16 of 16	NP_001244127.1
	CUL3	NM_001257197.2		c.*3026G>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.*3026G>A		3_prime_UTR	Exon 16 of 16	ENSP00000264414.4	Q13618-1
	CUL3	ENST00000344951.8	TSL:2	c.*3026G>A		3_prime_UTR	Exon 15 of 15	ENSP00000343601.4	Q13618-3
	ENSG00000274629	ENST00000620050.1	TSL:5	n.242-2762C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152110 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

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: 0.0000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000340 AC: 20 AN: 58810 Hom.: 0 Cov.: 0 AF XY: 0.000293 AC XY: 8 AN XY: 27258

African (AFR) AF: 0.00 AC: 0 AN: 2710

American (AMR) AF: 0.00 AC: 0 AN: 1770

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3714

East Asian (EAS) AF: 0.00 AC: 0 AN: 8694

South Asian (SAS) AF: 0.00 AC: 0 AN: 490

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 368

European-Non Finnish (NFE) AF: 0.000527 AC: 19 AN: 36076

Other (OTH) AF: 0.000202 AC: 1 AN: 4950

GnomAD4 genome AF: 0.000309 AC: 47 AN: 152110 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74306

African (AFR) AF: 0.0000724 AC: 3 AN: 41422

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000944 AC: 1 AN: 10588

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

European-Non Finnish (NFE) AF: 0.000632 AC: 43 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000318 Hom.: 0

Bravo AF: 0.000283

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	-0.79
CADD	Benign	4.0
DANN	Benign	0.72
PhyloP100		-0.49

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: rs748865811; hg19: chr2-225335936;