rs41529948

Variant names:

• chr2-224471300-C-G
• rs41529948
• NM_003590.5:c.*2945G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-224471300-C-G
• chr2-224471300-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003590.5(CUL3):​c.*2945G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00441 in 204,628 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0051 (1 hom.)
• Consequence: CUL3 NM_003590.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0330
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-224471300-C-G is Benign according to our data. Variant chr2-224471300-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 334586.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00418 (636/152176) while in subpopulation NFE AF = 0.00677 (460/67982). AF 95% confidence interval is 0.00626. There are 2 homozygotes in GnomAd4. There are 308 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 636 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.*2945G>C		3_prime_UTR	Exon 16 of 16	NP_003581.1	Q13618-1
	CUL3	NM_001257198.2		c.*2945G>C		3_prime_UTR	Exon 16 of 16	NP_001244127.1
	CUL3	NM_001257197.2		c.*2945G>C		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.*2945G>C		3_prime_UTR	Exon 16 of 16	ENSP00000264414.4	Q13618-1
	CUL3	ENST00000344951.8	TSL:2	c.*2945G>C		3_prime_UTR	Exon 15 of 15	ENSP00000343601.4	Q13618-3
	ENSG00000274629	ENST00000620050.1	TSL:5	n.242-2681C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00419 AC: 637 AN: 152058 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00603

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00678

Gnomad OTH AF: 0.00860

GnomAD4 exome AF: 0.00509 AC: 267 AN: 52452 Hom.: 1 Cov.: 0 AF XY: 0.00510 AC XY: 124 AN XY: 24306

African (AFR) AF: 0.000424 AC: 1 AN: 2358

American (AMR) AF: 0.00584 AC: 9 AN: 1540

Ashkenazi Jewish (ASJ) AF: 0.000297 AC: 1 AN: 3362

East Asian (EAS) AF: 0.00 AC: 0 AN: 8030

South Asian (SAS) AF: 0.00 AC: 0 AN: 432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40

Middle Eastern (MID) AF: 0.00307 AC: 1 AN: 326

European-Non Finnish (NFE) AF: 0.00713 AC: 228 AN: 31990

Other (OTH) AF: 0.00617 AC: 27 AN: 4374

GnomAD4 genome AF: 0.00418 AC: 636 AN: 152176 Hom.: 2 Cov.: 33 AF XY: 0.00414 AC XY: 308 AN XY: 74414

African (AFR) AF: 0.00140 AC: 58 AN: 41526

American (AMR) AF: 0.00602 AC: 92 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4816

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10600

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00677 AC: 460 AN: 67982

Other (OTH) AF: 0.00851 AC: 18 AN: 2116

Alfa AF: 0.000694 Hom.: 0

Bravo AF: 0.00459

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.6
DANN	Benign	0.64
PhyloP100		-0.033
Mutation Taster		=100/0	polymorphism

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: rs41529948; hg19: chr2-225336017;