NM_003590.5:c.1849_1851delCAGinsGAA

Variant names:

• chr2-224482070-CTG-TTC
• NM_003590.5:c.1849_1851delCAGinsGAA
• CUL3 p.Gln617Glu

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_003590.5(CUL3):c.1849_1851delCAGinsGAA (p.Gln617Glu) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.Q617E: Uncertain_significance (ClinVar VariationId 2399057, 2 stars); p.Q617= (synonymous): Likely_benign (ClinVar VariationId 2874676, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CUL3 NM_003590.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0
• 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: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	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.1849_1851delCAGinsGAA p.Gln617Glu	missense	N/A	Prot: NP_003581.1 UniProt:
	CUL3 NM_001257198.2		c.1867_1869delCAGinsGAA p.Gln623Glu	missense	N/A	Prot: NP_001244127.1
	CUL3 NM_001257197.2		c.1651_1653delCAGinsGAA p.Gln551Glu	missense	N/A	Prot: NP_001244126.1 UniProt:

CUL3 NM_003590.5

MANE Select

HGVSc / HGVSpc.1849_1851delCAGinsGAAp.Gln617Glu

Exon rankN/A

missense

Prot: NP_003581.1UniProt: Q13618-1

CUL3 NM_001257198.2

HGVSc / HGVSpc.1867_1869delCAGinsGAAp.Gln623Glu

Exon rankN/A

missense

Prot: NP_001244127.1

CUL3 NM_001257197.2

HGVSc / HGVSpc.1651_1653delCAGinsGAAp.Gln551Glu

Exon rankN/A

missense

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.1849_1851delCAGinsGAA p.Gln617Glu	missense	N/A	Prot: ENSP00000264414.4 UniProt:
	CUL3 ENST00000409096.5	TSL:1	c.1777_1779delCAGinsGAA p.Gln593Glu	missense	N/A	Prot: ENSP00000387200.1 UniProt:
	CUL3 ENST00000409777.5	TSL:1	c.1777_1779delCAGinsGAA p.Gln593Glu	missense	N/A	Prot: ENSP00000386525.1 UniProt:

CUL3 ENST00000264414.9

TSL:1MANE Select

HGVSc / HGVSpc.1849_1851delCAGinsGAAp.Gln617Glu

Exon rankN/A

missense

Prot: ENSP00000264414.4UniProt: Q13618-1

CUL3 ENST00000409096.5

TSL:1

HGVSc / HGVSpc.1777_1779delCAGinsGAAp.Gln593Glu

Exon rankN/A

missense

Prot: ENSP00000387200.1UniProt: Q13618-2

CUL3 ENST00000409777.5

TSL:1

HGVSc / HGVSpc.1777_1779delCAGinsGAAp.Gln593Glu

Exon rankN/A

missense

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	10

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr2-225346787;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar