rs2070127

Variant names:

• chr2-224481929-T-C
• rs2070127
• NM_003590.5:c.1992A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-224481929-T-C
• chr2-224481929-T-A
• chr2-224481929-T-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003590.5(CUL3):​c.1992A>G​(p.Gln664Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,588,794 control chromosomes in the GnomAD database, including 20,901 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2932 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17969 hom.)
• Consequence: CUL3 NM_003590.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.82
• Publications: 22 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-224481929-T-C is Benign according to our data. Variant chr2-224481929-T-C is described in ClinVar as Benign. ClinVar VariationId is 259092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.82 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.258 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.1992A>G	p.Gln664Gln	synonymous	Exon 14 of 16	NP_003581.1	Q13618-1
	CUL3	NM_001257198.2		c.2010A>G	p.Gln670Gln	synonymous	Exon 14 of 16	NP_001244127.1
	CUL3	NM_001257197.2		c.1794A>G	p.Gln598Gln	synonymous	Exon 13 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.1992A>G	p.Gln664Gln	synonymous	Exon 14 of 16	ENSP00000264414.4	Q13618-1
	CUL3	ENST00000409096.5	TSL:1	c.1920A>G	p.Gln640Gln	synonymous	Exon 14 of 16	ENSP00000387200.1	Q13618-2
	CUL3	ENST00000409777.5	TSL:1	c.1920A>G	p.Gln640Gln	synonymous	Exon 14 of 16	ENSP00000386525.1	Q13618-2

Frequencies

GnomAD3 genomes AF: 0.185 AC: 28047 AN: 151926 Hom.: 2922 Cov.: 32

Gnomad AFR AF: 0.259

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.271

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.130

Gnomad OTH AF: 0.185

GnomAD2 exomes AF: 0.184 AC: 43668 AN: 237076 AF XY: 0.182

Gnomad AFR exome AF: 0.262

Gnomad AMR exome AF: 0.246

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.274

Gnomad FIN exome AF: 0.158

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.169

GnomAD4 exome AF: 0.149 AC: 214367 AN: 1436750 Hom.: 17969 Cov.: 30 AF XY: 0.151 AC XY: 108058 AN XY: 713414

African (AFR) AF: 0.255 AC: 8259 AN: 32450

American (AMR) AF: 0.237 AC: 9819 AN: 41434

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 2903 AN: 25920

East Asian (EAS) AF: 0.292 AC: 11275 AN: 38624

South Asian (SAS) AF: 0.256 AC: 20378 AN: 79566

European-Finnish (FIN) AF: 0.160 AC: 8497 AN: 53250

Middle Eastern (MID) AF: 0.137 AC: 721 AN: 5256

European-Non Finnish (NFE) AF: 0.130 AC: 142822 AN: 1100750

Other (OTH) AF: 0.163 AC: 9693 AN: 59500

GnomAD4 genome AF: 0.185 AC: 28090 AN: 152044 Hom.: 2932 Cov.: 32 AF XY: 0.188 AC XY: 13994 AN XY: 74302

African (AFR) AF: 0.260 AC: 10763 AN: 41472

American (AMR) AF: 0.216 AC: 3295 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 383 AN: 3466

East Asian (EAS) AF: 0.268 AC: 1386 AN: 5176

South Asian (SAS) AF: 0.271 AC: 1305 AN: 4822

European-Finnish (FIN) AF: 0.150 AC: 1591 AN: 10590

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.130 AC: 8821 AN: 67928

Other (OTH) AF: 0.182 AC: 384 AN: 2108

Alfa AF: 0.144 Hom.: 2477

Bravo AF: 0.191

Asia WGS AF: 0.275 AC: 954 AN: 3478

ClinVar

ClinVar submissions

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
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.3
DANN	Benign	0.46
PhyloP100		1.8
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: rs2070127; hg19: chr2-225346646; COSMIC: COSV52361484; COSMIC: COSV52361484;