rs1553521389

Variant names:

• chr2-224503678-CAG-C
• rs1553521389
• NM_003590.5:c.1349_1350delCT

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 14 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2PP5_Strong

The NM_003590.5(CUL3):c.1349_1350delCT (p.Ser450fs) variant causes a frameshift change. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant has a gnomAD grpmax filtering allele frequency (95% CI) of 0.000000905, indicating it is observed in the general population. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.76). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CUL3 NM_003590.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.76
• 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, Labcorp Genetics (formerly Invitae), Ambry Genetics

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Frameshift (exon 9 of 16) at amino acid 450 of 768, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene. A new stop codon is introduced in the shifted frame, truncating the protein to ~449 amino acids (319 amino acids lost).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.000000905 — very rare for AD/XL gene (threshold 0.0001) — PM2 moderate.
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_003590.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CUL3 NM_003590.5	MANE Select	c.1349_1350delCT p.Ser450fs	frameshift	Exon 9 of 16	Prot: NP_003581.1 UniProt:
	CUL3 NM_001257198.2		c.1367_1368delCT p.Ser456fs	frameshift	Exon 9 of 16	Prot: NP_001244127.1
	CUL3 NM_001257197.2		c.1151_1152delCT p.Ser384fs	frameshift	Exon 8 of 15	Prot: NP_001244126.1 UniProt:

CUL3 NM_003590.5

MANE Select

HGVSc / HGVSpc.1349_1350delCTp.Ser450fs

Exon rankExon 9 of 16

frameshift

Prot: NP_003581.1UniProt: Q13618-1

CUL3 NM_001257198.2

HGVSc / HGVSpc.1367_1368delCTp.Ser456fs

Exon rankExon 9 of 16

frameshift

Prot: NP_001244127.1

CUL3 NM_001257197.2

HGVSc / HGVSpc.1151_1152delCTp.Ser384fs

Exon rankExon 8 of 15

frameshift

Prot: NP_001244126.1UniProt: Q13618-3

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CUL3 ENST00000264414.9	TSL:1MANE Select	c.1349_1350delCT p.Ser450fs	frameshift	Exon 9 of 16	Prot: ENSP00000264414.4 UniProt:
	CUL3 ENST00000409096.5	TSL:1	c.1277_1278delCT p.Ser426fs	frameshift	Exon 9 of 16	Prot: ENSP00000387200.1 UniProt:
	CUL3 ENST00000409777.5	TSL:1	c.1277_1278delCT p.Ser426fs	frameshift	Exon 9 of 16	Prot: ENSP00000386525.1 UniProt:

CUL3 ENST00000264414.9

TSL:1MANE Select

HGVSc / HGVSpc.1349_1350delCTp.Ser450fs

Exon rankExon 9 of 16

frameshift

Prot: ENSP00000264414.4UniProt: Q13618-1

CUL3 ENST00000409096.5

TSL:1

HGVSc / HGVSpc.1277_1278delCTp.Ser426fs

Exon rankExon 9 of 16

frameshift

Prot: ENSP00000387200.1UniProt: Q13618-2

CUL3 ENST00000409777.5

TSL:1

HGVSc / HGVSpc.1277_1278delCTp.Ser426fs

Exon rankExon 9 of 16

frameshift

Prot: ENSP00000386525.1UniProt: Q13618-2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome Warning	AF: 6.95e-7	AC:1	Hom:0	AN:1439128	Cov:
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Inborn genetic diseases (1)
1	-	-	Neurodevelopmental disorder with or without autism or seizures (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
Mutation Taster	N/A	0/200	disease causing (ClinVar)
PhyloP100	Pathogenic	7.8

Showing 2 of 2 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
SpliceAI score (max)	Benign	0.020	Details are displayed if max score is > 0.2

Showing 1 of 1 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1553521389;

hg19: chr2-225368395;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar