chr2-224503848-T-C

Variant names:

• chr2-224503848-T-C
• rs199469650
• NM_003590.5:c.1207-26A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_003590.5(CUL3):​c.1207-26A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). There are indicators that this mutation may affect the branch point..

• Frequency: Genomes: not found (cov: 33)
• Consequence: CUL3 NM_003590.5 intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 0.913
• Publications: 3 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-224503848-T-C is Pathogenic according to our data. Variant chr2-224503848-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 100517.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 4 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.47). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL3	NM_003590.5	c.1207-26A>G		intron_variant	Intron 8 of 15	ENST00000264414.9	NP_003581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL3	ENST00000264414.9	c.1207-26A>G		intron_variant	Intron 8 of 15	1	NM_003590.5	ENSP00000264414.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Jun 12, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate the variant leads to an in-frame deletion consistent with exon 9 skipping, resulting in a gain of function effect (PMID: 22266938, 25250572); Not observed at significant frequency in large population cohorts (gnomAD); De novo variant with confirmed parentage in a patient referred for genetic testing at GeneDx; however, the reported clinical features are only partially consistent with the features typically observed in individuals with pathogenic variants in this gene; This variant is associated with the following publications: (PMID: 23453970, 25250572, 31802109, 22266938) -

Pseudohypoaldosteronism type 2E Pathogenic:1

Jan 22, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Pseudohypoaldosteronism type 2A Pathogenic:1

-

Richard Lifton Laboratory, Yale University School of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.9
DANN	Benign	0.75
PhyloP100		0.91
La Branchor		0.42
BranchPoint Hunter		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs199469650; hg19: chr2-225368565;