chr2-224482072-G-C

Variant names:

• chr2-224482072-G-C
• rs969388164
• NM_003590.5:c.1849C>G
• 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.1849C>G (p.Gln617Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000131 (AC=2) in the gnomAD database across 152,128 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000488. 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). Variant has been reported in ClinVar as Uncertain Significance (★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): 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: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: CUL3 NM_003590.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000488 — very rare for AD/XL gene (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>G p.Gln617Glu	missense	Exon 14 of 16	Prot: NP_003581.1 UniProt:
	CUL3 NM_001257198.2		c.1867C>G p.Gln623Glu	missense	Exon 14 of 16	Prot: NP_001244127.1
	CUL3 NM_001257197.2		c.1651C>G p.Gln551Glu	missense	Exon 13 of 15	Prot: NP_001244126.1 UniProt:

CUL3 NM_003590.5

MANE Select

HGVSc / HGVSpc.1849C>Gp.Gln617Glu

Exon rankExon 14 of 16

missense

Prot: NP_003581.1UniProt: Q13618-1

CUL3 NM_001257198.2

HGVSc / HGVSpc.1867C>Gp.Gln623Glu

Exon rankExon 14 of 16

missense

Prot: NP_001244127.1

CUL3 NM_001257197.2

HGVSc / HGVSpc.1651C>Gp.Gln551Glu

Exon rankExon 13 of 15

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.1849C>G p.Gln617Glu	missense	Exon 14 of 16	Prot: ENSP00000264414.4 UniProt:
	CUL3 ENST00000409096.5	TSL:1	c.1777C>G p.Gln593Glu	missense	Exon 14 of 16	Prot: ENSP00000387200.1 UniProt:
	CUL3 ENST00000409777.5	TSL:1	c.1777C>G p.Gln593Glu	missense	Exon 14 of 16	Prot: ENSP00000386525.1 UniProt:

CUL3 ENST00000264414.9

TSL:1MANE Select

HGVSc / HGVSpc.1849C>Gp.Gln617Glu

Exon rankExon 14 of 16

missense

Prot: ENSP00000264414.4UniProt: Q13618-1

CUL3 ENST00000409096.5

TSL:1

HGVSc / HGVSpc.1777C>Gp.Gln593Glu

Exon rankExon 14 of 16

missense

Prot: ENSP00000387200.1UniProt: Q13618-2

CUL3 ENST00000409777.5

TSL:1

HGVSc / HGVSpc.1777C>Gp.Gln593Glu

Exon rankExon 14 of 16

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 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000131	AC:2	Hom:0	AN:152128	Cov:32
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:30
GnomAD4 genome	AF: 0.0000131	AC:2	Hom:0	AN:152128	Cov:32
TOPMed (Bravo)	AF: 0.0000189	AC:5	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000594	AC:1	Hom:0	AN:16840	Cov:

Showing 5 sources

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Pseudohypoaldosteronism type 2E;C5543225:Neurodevelopmental disorder with or without autism or seizures (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	29
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	23
DANN	Benign	0.65
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
FuncVEP CTI	Benign	0.041
GPN-Star LLR	N/A	-8.9
GPN-Star score	N/A	8.9
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.63	T
Mutation Taster	N/A	75/25	polymorphism
MutationAssessor	Benign	1.1	L
PhyloP100	Pathogenic	10
popEVE	Benign	-3.7
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.65	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.1
REVEL	Uncertain	0.33
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Varity_R	N/A	0.28
VESM-3B	Benign	-7.7

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 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;

COSMIC: COSV109408358;

COSMIC: COSV109408358;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar