X-120530182-G-A

Variant names:

• chrX-120530182-G-A
• NM_001079872.2:c.2512C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001079872.2(CUL4B):​c.2512C>T​(p.Arg838*) variant causes a stop gained 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CUL4B NM_001079872.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.88
• 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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-120530182-G-A is Pathogenic according to our data. Variant chrX-120530182-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4075063.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL4B	NM_001079872.2	c.2512C>T	p.Arg838*	stop_gained	Exon 19 of 20	ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4	c.2566C>T	p.Arg856*	stop_gained	Exon 21 of 22		NP_003579.3
CUL4B	NM_001330624.2	c.2527C>T	p.Arg843*	stop_gained	Exon 20 of 21		NP_001317553.1
CUL4B	NM_001369145.1	c.1978C>T	p.Arg660*	stop_gained	Exon 19 of 20		NP_001356074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.2512C>T	p.Arg838*	stop_gained	Exon 19 of 20	1	NM_001079872.2	ENSP00000360373.5
CUL4B	ENST00000681206.1	c.2626C>T	p.Arg876*	stop_gained	Exon 22 of 23			ENSP00000505480.1
CUL4B	ENST00000680673.1	c.2566C>T	p.Arg856*	stop_gained	Exon 21 of 22			ENSP00000505084.1
CUL4B	ENST00000681253.1	c.2566C>T	p.Arg856*	stop_gained	Exon 22 of 23			ENSP00000506259.1
CUL4B	ENST00000681652.1	c.2566C>T	p.Arg856*	stop_gained	Exon 24 of 25			ENSP00000505176.1
CUL4B	ENST00000336592.11	c.2527C>T	p.Arg843*	stop_gained	Exon 20 of 21	5		ENSP00000338919.6
CUL4B	ENST00000674137.11	c.2518C>T	p.Arg840*	stop_gained	Exon 19 of 20			ENSP00000501019.6
CUL4B	ENST00000681090.1	c.2419C>T	p.Arg807*	stop_gained	Exon 19 of 20			ENSP00000506288.1
CUL4B	ENST00000679927.1	c.2167C>T	p.Arg723*	stop_gained	Exon 20 of 21			ENSP00000505603.1
CUL4B	ENST00000371323.3	c.1978C>T	p.Arg660*	stop_gained	Exon 19 of 20	5		ENSP00000360374.3
CUL4B	ENST00000680474.1	c.1954C>T	p.Arg652*	stop_gained	Exon 18 of 20			ENSP00000505562.1
CUL4B	ENST00000679844.1	c.1849C>T	p.Arg617*	stop_gained	Exon 17 of 18			ENSP00000505239.1
CUL4B	ENST00000673919.1	n.*1959C>T		non_coding_transcript_exon_variant	Exon 20 of 21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.*68C>T		non_coding_transcript_exon_variant	Exon 17 of 18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1721C>T		non_coding_transcript_exon_variant	Exon 21 of 22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1721C>T		non_coding_transcript_exon_variant	Exon 21 of 22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*1428C>T		non_coding_transcript_exon_variant	Exon 17 of 18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1721C>T		non_coding_transcript_exon_variant	Exon 19 of 20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*678C>T		non_coding_transcript_exon_variant	Exon 19 of 20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*3405C>T		non_coding_transcript_exon_variant	Exon 16 of 17			ENSP00000505739.1
CUL4B	ENST00000681908.1	n.*684C>T		non_coding_transcript_exon_variant	Exon 19 of 20			ENSP00000505777.1
CUL4B	ENST00000673919.1	n.*1959C>T		3_prime_UTR_variant	Exon 20 of 21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.*68C>T		3_prime_UTR_variant	Exon 17 of 18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1721C>T		3_prime_UTR_variant	Exon 21 of 22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1721C>T		3_prime_UTR_variant	Exon 21 of 22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*1428C>T		3_prime_UTR_variant	Exon 17 of 18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1721C>T		3_prime_UTR_variant	Exon 19 of 20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*678C>T		3_prime_UTR_variant	Exon 19 of 20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*3405C>T		3_prime_UTR_variant	Exon 16 of 17			ENSP00000505739.1
CUL4B	ENST00000681908.1	n.*684C>T		3_prime_UTR_variant	Exon 19 of 20			ENSP00000505777.1
CUL4B	ENST00000404115.8	c.2439+2240C>T		intron_variant	Intron 18 of 18	1		ENSP00000384109.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability Pathogenic:1

Sep 11, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	38
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		2.9
Vest4		0.83
GERP RS		4.4
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

hg19: chrX-119664037; COSMIC: COSV60684870; COSMIC: COSV60684870;