chr2-224482072-G-A

Variant names:

• chr2-224482072-G-A
• rs969388164
• NM_003590.5:c.1849C>T
• CUL3 p.Gln617*

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+10 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 10 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2

The NM_003590.5(CUL3):c.1849C>T (p.Gln617*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 10.00). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CUL3 NM_003590.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• Publications: 1 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 10 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); Stop-gained (exon 14 of 16) at amino acid 617 of 768, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene.
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.

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.1849C>T p.Gln617*	stop_gained	Exon 14 of 16	Prot: NP_003581.1 UniProt:
	CUL3 NM_001257198.2		c.1867C>T p.Gln623*	stop_gained	Exon 14 of 16	Prot: NP_001244127.1
	CUL3 NM_001257197.2		c.1651C>T p.Gln551*	stop_gained	Exon 13 of 15	Prot: NP_001244126.1 UniProt:

CUL3 NM_003590.5

MANE Select

HGVSc / HGVSpc.1849C>Tp.Gln617*

Exon rankExon 14 of 16

stop_gained

Prot: NP_003581.1UniProt: Q13618-1

CUL3 NM_001257198.2

HGVSc / HGVSpc.1867C>Tp.Gln623*

Exon rankExon 14 of 16

stop_gained

Prot: NP_001244127.1

CUL3 NM_001257197.2

HGVSc / HGVSpc.1651C>Tp.Gln551*

Exon rankExon 13 of 15

stop_gained

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.1849C>T p.Gln617*	stop_gained	Exon 14 of 16	Prot: ENSP00000264414.4 UniProt:
	CUL3 ENST00000409096.5	TSL:1	c.1777C>T p.Gln593*	stop_gained	Exon 14 of 16	Prot: ENSP00000387200.1 UniProt:
	CUL3 ENST00000409777.5	TSL:1	c.1777C>T p.Gln593*	stop_gained	Exon 14 of 16	Prot: ENSP00000386525.1 UniProt:

CUL3 ENST00000264414.9

TSL:1MANE Select

HGVSc / HGVSpc.1849C>Tp.Gln617*

Exon rankExon 14 of 16

stop_gained

Prot: ENSP00000264414.4UniProt: Q13618-1

CUL3 ENST00000409096.5

TSL:1

HGVSc / HGVSpc.1777C>Tp.Gln593*

Exon rankExon 14 of 16

stop_gained

Prot: ENSP00000387200.1UniProt: Q13618-2

CUL3 ENST00000409777.5

TSL:1

HGVSc / HGVSpc.1777C>Tp.Gln593*

Exon rankExon 14 of 16

stop_gained

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:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	47
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	48
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
GPN-Star LLR	N/A	-10
GPN-Star score	N/A	10
Mutation Taster	N/A	7/193	disease causing (fs/PTC)
PhyloP100	Pathogenic	10

Showing 12 of 12 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Uncertain	0.25
Pangolin loss	Uncertain	0.25	Position offset: 6
SpliceAI score (max)	Benign	0.050	Details are displayed if max score is > 0.2

Showing 3 of 3 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: rs969388164;

hg19: chr2-225346789;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar