rs3738952

Variant names:

• chr2-224497761-C-T
• rs3738952
• NM_003590.5:c.1699G>A

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.1699G>A​(p.Val567Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,609,540 control chromosomes in the GnomAD database, including 10,865 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.091 (877 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9988 hom.)
• Consequence: CUL3 NM_003590.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.69
• Publications: 40 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)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001349926).
• BP6: Variant 2-224497761-C-T is Benign according to our data. Variant chr2-224497761-C-T is described in ClinVar as Benign. ClinVar VariationId is 259091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.255 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.1699G>A	p.Val567Ile	missense	Exon 12 of 16	NP_003581.1	Q13618-1
	CUL3	NM_001257198.2		c.1717G>A	p.Val573Ile	missense	Exon 12 of 16	NP_001244127.1
	CUL3	NM_001257197.2		c.1501G>A	p.Val501Ile	missense	Exon 11 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.1699G>A	p.Val567Ile	missense	Exon 12 of 16	ENSP00000264414.4	Q13618-1
	CUL3	ENST00000409096.5	TSL:1	c.1627G>A	p.Val543Ile	missense	Exon 12 of 16	ENSP00000387200.1	Q13618-2
	CUL3	ENST00000409777.5	TSL:1	c.1627G>A	p.Val543Ile	missense	Exon 12 of 16	ENSP00000386525.1	Q13618-2

Frequencies

GnomAD3 genomes AF: 0.0906 AC: 13772 AN: 152070 Hom.: 878 Cov.: 32

Gnomad AFR AF: 0.0276

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.0631

Gnomad EAS AF: 0.266

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.0950

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0910

Gnomad OTH AF: 0.103

GnomAD2 exomes AF: 0.131 AC: 32960 AN: 250984 AF XY: 0.131

Gnomad AFR exome AF: 0.0255

Gnomad AMR exome AF: 0.212

Gnomad ASJ exome AF: 0.0641

Gnomad EAS exome AF: 0.270

Gnomad FIN exome AF: 0.0971

Gnomad NFE exome AF: 0.0950

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.105 AC: 153367 AN: 1457352 Hom.: 9988 Cov.: 29 AF XY: 0.107 AC XY: 77881 AN XY: 725306

African (AFR) AF: 0.0227 AC: 757 AN: 33398

American (AMR) AF: 0.205 AC: 9167 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0654 AC: 1706 AN: 26098

East Asian (EAS) AF: 0.290 AC: 11475 AN: 39634

South Asian (SAS) AF: 0.187 AC: 16132 AN: 86086

European-Finnish (FIN) AF: 0.102 AC: 5435 AN: 53372

Middle Eastern (MID) AF: 0.100 AC: 579 AN: 5762

European-Non Finnish (NFE) AF: 0.0915 AC: 101396 AN: 1108080

Other (OTH) AF: 0.112 AC: 6720 AN: 60220

GnomAD4 genome AF: 0.0905 AC: 13778 AN: 152188 Hom.: 877 Cov.: 32 AF XY: 0.0936 AC XY: 6964 AN XY: 74390

African (AFR) AF: 0.0276 AC: 1146 AN: 41536

American (AMR) AF: 0.166 AC: 2537 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0631 AC: 219 AN: 3472

East Asian (EAS) AF: 0.266 AC: 1380 AN: 5182

South Asian (SAS) AF: 0.202 AC: 974 AN: 4814

European-Finnish (FIN) AF: 0.0950 AC: 1006 AN: 10590

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0910 AC: 6187 AN: 67996

Other (OTH) AF: 0.101 AC: 213 AN: 2110

Alfa AF: 0.0959 Hom.: 3733

Bravo AF: 0.0941

TwinsUK AF: 0.0882 AC: 327

ALSPAC AF: 0.0895 AC: 345

ESP6500AA AF: 0.0261 AC: 115

ESP6500EA AF: 0.0943 AC: 811

ExAC AF: 0.128 AC: 15533

Asia WGS AF: 0.240 AC: 834 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Autosomal dominant pseudohypoaldosteronism type 1 (1)
-	-	1	not specified (1)
-	-	1	Pseudohypoaldosteronism type 2E (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		2.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.21
Sift	Benign	0.19	T
Sift4G	Benign	0.19	T
Polyphen		0.0	B
Vest4		0.15
MPC		0.95
ClinPred		0.016	T
GERP RS		6.2
PromoterAI		-0.012	Neutral
Varity_R		0.081
gMVP		0.095
Mutation Taster		=98/2	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: rs3738952; hg19: chr2-225362478; COSMIC: COSV52361494; COSMIC: COSV52361494;