rs1556200641

Variant names:

• chrX-120538726-G-A
• rs1556200641
• NM_001079872.2:c.1786C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001079872.2(CUL4B):​c.1786C>T​(p.Arg596Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CUL4B NM_001079872.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 2.57

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant X-120538726-G-A is Pathogenic according to our data. Variant chrX-120538726-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 434873.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL4B	NM_001079872.2	c.1786C>T	p.Arg596Cys	missense_variant	Exon 13 of 20	ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4	c.1840C>T	p.Arg614Cys	missense_variant	Exon 15 of 22		NP_003579.3
CUL4B	NM_001330624.2	c.1801C>T	p.Arg601Cys	missense_variant	Exon 14 of 21		NP_001317553.1
CUL4B	NM_001369145.1	c.1252C>T	p.Arg418Cys	missense_variant	Exon 13 of 20		NP_001356074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.1786C>T	p.Arg596Cys	missense_variant	Exon 13 of 20	1	NM_001079872.2	ENSP00000360373.5
CUL4B	ENST00000681206.1	c.1900C>T	p.Arg634Cys	missense_variant	Exon 16 of 23			ENSP00000505480.1
CUL4B	ENST00000680673.1	c.1840C>T	p.Arg614Cys	missense_variant	Exon 15 of 22			ENSP00000505084.1
CUL4B	ENST00000681253.1	c.1840C>T	p.Arg614Cys	missense_variant	Exon 16 of 23			ENSP00000506259.1
CUL4B	ENST00000681652.1	c.1840C>T	p.Arg614Cys	missense_variant	Exon 18 of 25			ENSP00000505176.1
CUL4B	ENST00000336592.11	c.1801C>T	p.Arg601Cys	missense_variant	Exon 14 of 21	5		ENSP00000338919.6
CUL4B	ENST00000674137.11	c.1786C>T	p.Arg596Cys	missense_variant	Exon 13 of 20			ENSP00000501019.6
CUL4B	ENST00000681090.1	c.1693C>T	p.Arg565Cys	missense_variant	Exon 13 of 20			ENSP00000506288.1
CUL4B	ENST00000404115.8	c.1786C>T	p.Arg596Cys	missense_variant	Exon 13 of 19	1		ENSP00000384109.4
CUL4B	ENST00000679927.1	c.1441C>T	p.Arg481Cys	missense_variant	Exon 14 of 21			ENSP00000505603.1
CUL4B	ENST00000371323.3	c.1252C>T	p.Arg418Cys	missense_variant	Exon 13 of 20	5		ENSP00000360374.3
CUL4B	ENST00000680474.1	c.1228C>T	p.Arg410Cys	missense_variant	Exon 12 of 20			ENSP00000505562.1
CUL4B	ENST00000679844.1	c.1123C>T	p.Arg375Cys	missense_variant	Exon 11 of 18			ENSP00000505239.1
CUL4B	ENST00000673919.1	n.*1233C>T		non_coding_transcript_exon_variant	Exon 14 of 21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.1228C>T		non_coding_transcript_exon_variant	Exon 12 of 18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*995C>T		non_coding_transcript_exon_variant	Exon 15 of 22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*995C>T		non_coding_transcript_exon_variant	Exon 15 of 22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*702C>T		non_coding_transcript_exon_variant	Exon 11 of 18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*995C>T		non_coding_transcript_exon_variant	Exon 13 of 20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.1228C>T		non_coding_transcript_exon_variant	Exon 12 of 20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*2229C>T		non_coding_transcript_exon_variant	Exon 11 of 17			ENSP00000505739.1
CUL4B	ENST00000681869.1	n.1228C>T		non_coding_transcript_exon_variant	Exon 12 of 17			ENSP00000505597.1
CUL4B	ENST00000681908.1	n.1228C>T		non_coding_transcript_exon_variant	Exon 12 of 20			ENSP00000505777.1
CUL4B	ENST00000673919.1	n.*1233C>T		3_prime_UTR_variant	Exon 14 of 21			ENSP00000500994.1
CUL4B	ENST00000679405.1	n.*995C>T		3_prime_UTR_variant	Exon 15 of 22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*995C>T		3_prime_UTR_variant	Exon 15 of 22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*702C>T		3_prime_UTR_variant	Exon 11 of 18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*995C>T		3_prime_UTR_variant	Exon 13 of 20			ENSP00000505898.1
CUL4B	ENST00000681333.1	n.*2229C>T		3_prime_UTR_variant	Exon 11 of 17			ENSP00000505739.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

X-linked intellectual disability Cabezas type Pathogenic:1

-

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been previously reported or functionally characterized in the literature to our knowledge. The CUL4B gene is constrained against variation (Z-score= 3.77 and pLI = 1), and missense variants are a common mechanism of disease (PMID: 25385192, 17236139). The c.1840C>T (p.Arg614Cys) variant is absent from the gnomAD population database and thus is presumed to be rare. The c.1840C>T (p.Arg614Cys) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.1840C>T (p.Arg614Cys) variant is classified as Likely Pathogenic. -

not specified Uncertain:1

Sep 28, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	.;.;D
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.1	.;.;H
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-7.5	D;D;D
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.77
MutPred		0.91		.;.;Gain of catalytic residue at L615 (P = 0.0125);
MVP		1.0
MPC		3.5
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs1556200641; hg19: chrX-119672581;