chr2-224470508-TA-T

Variant names:

• chr2-224470508-TA-T
• rs5839066
• NM_003590.5:c.*3736delT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_003590.5(CUL3):​c.*3736delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 231,280 control chromosomes in the GnomAD database, including 4,170 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.18 (2933 hom., cov: 29)
  • Exomes 𝑓: 0.16 (1237 hom.)
• Consequence: CUL3 NM_003590.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.00900
• Publications: 2 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 -10 ACMG points.

• BP6: Variant 2-224470508-TA-T is Benign according to our data. Variant chr2-224470508-TA-T is described in ClinVar as Benign. ClinVar VariationId is 334574.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.257 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.*3736delT		3_prime_UTR	Exon 16 of 16	NP_003581.1	Q13618-1
	CUL3	NM_001257198.2		c.*3736delT		3_prime_UTR	Exon 16 of 16	NP_001244127.1
	CUL3	NM_001257197.2		c.*3736delT		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.*3736delT		3_prime_UTR	Exon 16 of 16	ENSP00000264414.4	Q13618-1
	CUL3	ENST00000344951.8	TSL:2	c.*3736delT		3_prime_UTR	Exon 15 of 15	ENSP00000343601.4	Q13618-3
	ENSG00000274629	ENST00000620050.1	TSL:5	n.242-3471delA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.184 AC: 28006 AN: 152030 Hom.: 2922 Cov.: 29

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.215

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.181

GnomAD4 exome AF: 0.163 AC: 12925 AN: 79132 Hom.: 1237 Cov.: 0 AF XY: 0.163 AC XY: 5942 AN XY: 36392

African (AFR) AF: 0.234 AC: 890 AN: 3798

American (AMR) AF: 0.211 AC: 514 AN: 2438

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 584 AN: 5024

East Asian (EAS) AF: 0.303 AC: 3352 AN: 11074

South Asian (SAS) AF: 0.259 AC: 179 AN: 690

European-Finnish (FIN) AF: 0.0517 AC: 3 AN: 58

Middle Eastern (MID) AF: 0.138 AC: 66 AN: 478

European-Non Finnish (NFE) AF: 0.129 AC: 6317 AN: 48944

Other (OTH) AF: 0.154 AC: 1020 AN: 6628

GnomAD4 genome AF: 0.184 AC: 28051 AN: 152148 Hom.: 2933 Cov.: 29 AF XY: 0.188 AC XY: 13962 AN XY: 74358

African (AFR) AF: 0.260 AC: 10800 AN: 41494

American (AMR) AF: 0.215 AC: 3290 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 376 AN: 3468

East Asian (EAS) AF: 0.266 AC: 1374 AN: 5172

South Asian (SAS) AF: 0.269 AC: 1298 AN: 4820

European-Finnish (FIN) AF: 0.149 AC: 1584 AN: 10598

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

European-Non Finnish (NFE) AF: 0.129 AC: 8790 AN: 67980

Other (OTH) AF: 0.178 AC: 377 AN: 2114

Alfa AF: 0.157 Hom.: 250

Bravo AF: 0.191

Asia WGS AF: 0.276 AC: 959 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal dominant pseudohypoaldosteronism type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.0090
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: rs5839066; hg19: chr2-225335225;