2-224569728-A-G

Variant names:

• chr2-224569728-A-G
• rs10498163
• ENST00000409096.5:c.-46T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000409096.5(CUL3):​c.-46T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 1,209,746 control chromosomes in the GnomAD database, including 57,538 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6533 hom., cov: 31)
  • Exomes 𝑓: 0.31 (51005 hom.)
• Consequence: CUL3 ENST00000409096.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.835
• Publications: 14 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: Labcorp Genetics (formerly Invitae), G2P
• pseudohypoaldosteronism type 2E

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-224569728-A-G is Benign according to our data. Variant chr2-224569728-A-G is described in ClinVar as Benign. ClinVar VariationId is 504910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.329 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000409096.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL3	NM_003590.5	MANE Select	c.67-11872T>C		intron	N/A	NP_003581.1
	CUL3	NM_001257198.2		c.45T>C	p.His15His	synonymous	Exon 1 of 16	NP_001244127.1
	CUL3	NM_001257197.2		c.66+15216T>C		intron	N/A	NP_001244126.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL3	ENST00000409096.5	TSL:1	c.-46T>C		5_prime_UTR	Exon 1 of 16	ENSP00000387200.1
	CUL3	ENST00000264414.9	TSL:1 MANE Select	c.67-11872T>C		intron	N/A	ENSP00000264414.4
	CUL3	ENST00000344951.8	TSL:2	c.66+15216T>C		intron	N/A	ENSP00000343601.4

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43503 AN: 151772 Hom.: 6535 Cov.: 31

Gnomad AFR AF: 0.177

Gnomad AMI AF: 0.436

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.373

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.301

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.291

GnomAD2 exomes AF: 0.273 AC: 23123 AN: 84628 AF XY: 0.272

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.299

Gnomad ASJ exome AF: 0.342

Gnomad EAS exome AF: 0.229

Gnomad FIN exome AF: 0.270

Gnomad NFE exome AF: 0.290

Gnomad OTH exome AF: 0.288

GnomAD4 exome AF: 0.306 AC: 324205 AN: 1057856 Hom.: 51005 Cov.: 20 AF XY: 0.306 AC XY: 158532 AN XY: 518568

African (AFR) AF: 0.161 AC: 3298 AN: 20526

American (AMR) AF: 0.303 AC: 5190 AN: 17154

Ashkenazi Jewish (ASJ) AF: 0.361 AC: 4967 AN: 13752

East Asian (EAS) AF: 0.278 AC: 2273 AN: 8184

South Asian (SAS) AF: 0.244 AC: 15964 AN: 65506

European-Finnish (FIN) AF: 0.279 AC: 3156 AN: 11306

Middle Eastern (MID) AF: 0.331 AC: 1360 AN: 4104

European-Non Finnish (NFE) AF: 0.314 AC: 276412 AN: 879500

Other (OTH) AF: 0.306 AC: 11585 AN: 37824

GnomAD4 genome AF: 0.286 AC: 43504 AN: 151890 Hom.: 6533 Cov.: 31 AF XY: 0.287 AC XY: 21340 AN XY: 74242

African (AFR) AF: 0.177 AC: 7335 AN: 41462

American (AMR) AF: 0.333 AC: 5085 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.373 AC: 1295 AN: 3470

East Asian (EAS) AF: 0.323 AC: 1670 AN: 5174

South Asian (SAS) AF: 0.262 AC: 1265 AN: 4822

European-Finnish (FIN) AF: 0.301 AC: 3156 AN: 10492

Middle Eastern (MID) AF: 0.404 AC: 118 AN: 292

European-Non Finnish (NFE) AF: 0.332 AC: 22574 AN: 67906

Other (OTH) AF: 0.289 AC: 609 AN: 2106

Alfa AF: 0.323 Hom.: 4848

Bravo AF: 0.286

Asia WGS AF: 0.284 AC: 991 AN: 3470

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	7.8
DANN	Benign	0.65
PhyloP100		0.83
PromoterAI		-0.0072	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10498163; hg19: chr2-225434445; COSMIC: COSV52361378;