rs199469653

chr2-224503825-G-Achr2-224503825-G-Cchr2-224503825-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5 BP4

The NM_003590.5(CUL3):c.1207-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CUL3 NM_003590.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.2380
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 2.27

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP5: Variant 2-224503825-G-A is Pathogenic according to our data. Variant chr2-224503825-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 100519.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-224503825-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUL3	NM_003590.5	c.1207-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000264414.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUL3	ENST00000264414.9	c.1207-3C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_003590.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.25e-7 AC: 1 AN: 1379776 Hom.: 0 Cov.: 29 AF XY: 0.00000147 AC XY: 1 AN XY: 681984

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000344

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Pseudohypoaldosteronism type 2A Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Richard Lifton Laboratory, Yale University School of Medicine

-

- -

Pseudohypoaldosteronism type 2E Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 22, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
Cadd	Benign	16
Dann	Benign	0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.24
dbscSNV1_RF	Benign	0.11
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.26		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199469653; hg19: chr2-225368542;