rs374191606

Variant names:

• chr2-224470580-A-T
• rs374191606
• NM_003590.5:c.*3665T>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003590.5(CUL3):​c.*3665T>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 0.00162 in 231,650 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00055 (0 hom.)
• Consequence: CUL3 NM_003590.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.0370
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-224470580-A-T is Benign according to our data. Variant chr2-224470580-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 334576.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00217 (331/152354) while in subpopulation AFR AF = 0.00717 (298/41578). AF 95% confidence interval is 0.0065. There are 4 homozygotes in GnomAd4. There are 151 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 331 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.*3665T>A		3_prime_UTR	Exon 16 of 16	NP_003581.1	Q13618-1
	CUL3	NM_001257198.2		c.*3665T>A		3_prime_UTR	Exon 16 of 16	NP_001244127.1
	CUL3	NM_001257197.2		c.*3665T>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.*3665T>A		3_prime_UTR	Exon 16 of 16	ENSP00000264414.4	Q13618-1
	CUL3	ENST00000344951.8	TSL:2	c.*3665T>A		3_prime_UTR	Exon 15 of 15	ENSP00000343601.4	Q13618-3
	ENSG00000274629	ENST00000620050.1	TSL:5	n.242-3401A>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00212 AC: 323 AN: 152236 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000555 AC: 44 AN: 79296 Hom.: 0 Cov.: 0 AF XY: 0.000576 AC XY: 21 AN XY: 36474

African (AFR) AF: 0.00445 AC: 17 AN: 3822

American (AMR) AF: 0.000407 AC: 1 AN: 2456

Ashkenazi Jewish (ASJ) AF: 0.00318 AC: 16 AN: 5032

East Asian (EAS) AF: 0.00 AC: 0 AN: 11068

South Asian (SAS) AF: 0.00 AC: 0 AN: 682

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 58

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 476

European-Non Finnish (NFE) AF: 0.000102 AC: 5 AN: 49070

Other (OTH) AF: 0.000754 AC: 5 AN: 6632

GnomAD4 genome AF: 0.00217 AC: 331 AN: 152354 Hom.: 4 Cov.: 33 AF XY: 0.00203 AC XY: 151 AN XY: 74506

African (AFR) AF: 0.00717 AC: 298 AN: 41578

American (AMR) AF: 0.000980 AC: 15 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00166 Hom.: 0

Bravo AF: 0.00242

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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	-0.86
CADD	Benign	2.3
DANN	Benign	0.74
PhyloP100		0.037

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: rs374191606; hg19: chr2-225335297;