rs1260356990

Variant names:

• chrX-120543779-G-C
• rs1260356990
• NM_001079872.2:c.1204C>G

Your query was ambiguous. Multiple possible variants found:

• chrX-120543779-G-C
• chrX-120543779-G-A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001079872.2(CUL4B):​c.1204C>G​(p.Arg402Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CUL4B NM_001079872.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.88
• Publications: 0 publications found

Genes affected

CUL4B (HGNC:2555): (cullin 4B) This gene is a member of the cullin family. The encoded protein forms a complex that functions as an E3 ubiquitin ligase and catalyzes the polyubiquitination of specific protein substrates in the cell. The protein interacts with a ring finger protein, and is required for the proteolysis of several regulators of DNA replication including chromatin licensing and DNA replication factor 1 and cyclin E. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

CUL4B Gene-Disease associations (from GenCC):

• X-linked intellectual disability, Cabezas type

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943
• PP5: Variant X-120543779-G-C is Pathogenic according to our data. Variant chrX-120543779-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 520600.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079872.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL4B	NM_001079872.2	MANE Select	c.1204C>G	p.Arg402Gly	missense	Exon 8 of 20	NP_001073341.1	Q13620-1
	CUL4B	NM_003588.4		c.1258C>G	p.Arg420Gly	missense	Exon 10 of 22	NP_003579.3
	CUL4B	NM_001330624.2		c.1219C>G	p.Arg407Gly	missense	Exon 9 of 21	NP_001317553.1	K4DI93

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL4B	ENST00000371322.11	TSL:1 MANE Select	c.1204C>G	p.Arg402Gly	missense	Exon 8 of 20	ENSP00000360373.5	Q13620-1
	CUL4B	ENST00000681206.1		c.1318C>G	p.Arg440Gly	missense	Exon 11 of 23	ENSP00000505480.1	A0A7P0T954
	CUL4B	ENST00000680673.1		c.1258C>G	p.Arg420Gly	missense	Exon 10 of 22	ENSP00000505084.1	Q13620-2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.7	H
PhyloP100		9.9
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.75		Gain of glycosylation at K419 (P = 0.0502)
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.98
Mutation Taster		=23/77	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1260356990; hg19: chrX-119677634;