NM_001079872.2:c.1857C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001079872.2(CUL4B):c.1857C>T(p.Cys619Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,156,497 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 558 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., 36 hem., cov: 23)

Exomes 𝑓: 0.0014 ( 0 hom. 522 hem. )

Consequence

CUL4B
NM_001079872.2 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.73

Publications

1 publications found

Variant links:

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

CUL4B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant X-120538205-G-A is Benign according to our data. Variant chrX-120538205-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 194630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.73 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00114 (127/111794) while in subpopulation SAS AF = 0.00476 (13/2730). AF 95% confidence interval is 0.00282. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 36 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL4B	NM_001079872.2 link	c.1857C>T	p.Cys619Cys	synonymous_variant	Exon 14 of 20	ENST00000371322.11	NP_001073341.1	Q13620-1
CUL4B	NM_003588.4 link	c.1911C>T	p.Cys637Cys	synonymous_variant	Exon 16 of 22		NP_003579.3	Q13620-2
CUL4B	NM_001330624.2 link	c.1872C>T	p.Cys624Cys	synonymous_variant	Exon 15 of 21		NP_001317553.1	K4DI93
CUL4B	NM_001369145.1 link	c.1323C>T	p.Cys441Cys	synonymous_variant	Exon 14 of 20		NP_001356074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CUL4B	ENST00000371322.11 link	c.1857C>T	p.Cys619Cys	synonymous_variant	Exon 14 of 20	1	NM_001079872.2	ENSP00000360373.5	Q13620-1
CUL4B	ENST00000681206.1 link	c.1971C>T	p.Cys657Cys	synonymous_variant	Exon 17 of 23			ENSP00000505480.1	A0A7P0T954
CUL4B	ENST00000680673.1 link	c.1911C>T	p.Cys637Cys	synonymous_variant	Exon 16 of 22			ENSP00000505084.1	Q13620-2
CUL4B	ENST00000681253.1 link	c.1911C>T	p.Cys637Cys	synonymous_variant	Exon 17 of 23			ENSP00000506259.1	Q13620-2
CUL4B	ENST00000681652.1 link	c.1911C>T	p.Cys637Cys	synonymous_variant	Exon 19 of 25			ENSP00000505176.1	Q13620-2
CUL4B	ENST00000336592.11 link	c.1872C>T	p.Cys624Cys	synonymous_variant	Exon 15 of 21	5		ENSP00000338919.6	K4DI93
CUL4B	ENST00000674137.11 link	c.1857C>T	p.Cys619Cys	synonymous_variant	Exon 14 of 20			ENSP00000501019.6	A0A669KAX4
CUL4B	ENST00000681090.1 link	c.1764C>T	p.Cys588Cys	synonymous_variant	Exon 14 of 20			ENSP00000506288.1	A0A7P0TAQ3
CUL4B	ENST00000404115.8 link	c.1857C>T	p.Cys619Cys	synonymous_variant	Exon 14 of 19	1		ENSP00000384109.4	A0A804CL36
CUL4B	ENST00000679927.1 link	c.1512C>T	p.Cys504Cys	synonymous_variant	Exon 15 of 21			ENSP00000505603.1	A0A7P0T9L3
CUL4B	ENST00000371323.3 link	c.1323C>T	p.Cys441Cys	synonymous_variant	Exon 14 of 20	5		ENSP00000360374.3	Q13620-3
CUL4B	ENST00000680474.1 link	c.1299C>T	p.Cys433Cys	synonymous_variant	Exon 13 of 20			ENSP00000505562.1	A0A7P0T9C8
CUL4B	ENST00000679844.1 link	c.1194C>T	p.Cys398Cys	synonymous_variant	Exon 12 of 18			ENSP00000505239.1	A0A7P0T8P8
CUL4B	ENST00000673919.1 link	n.*1304C>T		non_coding_transcript_exon_variant	Exon 15 of 21			ENSP00000500994.1	A0A669KAU9
CUL4B	ENST00000674073.2 link	n.1299C>T		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000501262.2	A0A669KBG9
CUL4B	ENST00000679405.1 link	n.*1066C>T		non_coding_transcript_exon_variant	Exon 16 of 22			ENSP00000504985.1	A0A7P0Z439
CUL4B	ENST00000679432.1 link	n.*1066C>T		non_coding_transcript_exon_variant	Exon 16 of 22			ENSP00000505343.1	A0A7P0T8W4
CUL4B	ENST00000680918.1 link	n.*773C>T		non_coding_transcript_exon_variant	Exon 12 of 18			ENSP00000505955.1	A0A7P0Z4G9
CUL4B	ENST00000681080.1 link	n.*1066C>T		non_coding_transcript_exon_variant	Exon 14 of 20			ENSP00000505898.1	A0A7P0Z4E4
CUL4B	ENST00000681189.1 link	n.*23C>T		non_coding_transcript_exon_variant	Exon 14 of 20			ENSP00000505973.1	A0A7P0TAF9
CUL4B	ENST00000681333.1 link	n.*2750C>T		non_coding_transcript_exon_variant	Exon 11 of 17			ENSP00000505739.1	A0A7P0T9R8
CUL4B	ENST00000681869.1 link	n.1299C>T		non_coding_transcript_exon_variant	Exon 13 of 17			ENSP00000505597.1	A0A7P0T9D0
CUL4B	ENST00000681908.1 link	n.1299C>T		non_coding_transcript_exon_variant	Exon 13 of 20			ENSP00000505777.1	A0A7P0T9P5
CUL4B	ENST00000673919.1 link	n.*1304C>T		3_prime_UTR_variant	Exon 15 of 21			ENSP00000500994.1	A0A669KAU9
CUL4B	ENST00000679405.1 link	n.*1066C>T		3_prime_UTR_variant	Exon 16 of 22			ENSP00000504985.1	A0A7P0Z439
CUL4B	ENST00000679432.1 link	n.*1066C>T		3_prime_UTR_variant	Exon 16 of 22			ENSP00000505343.1	A0A7P0T8W4
CUL4B	ENST00000680918.1 link	n.*773C>T		3_prime_UTR_variant	Exon 12 of 18			ENSP00000505955.1	A0A7P0Z4G9
CUL4B	ENST00000681080.1 link	n.*1066C>T		3_prime_UTR_variant	Exon 14 of 20			ENSP00000505898.1	A0A7P0Z4E4
CUL4B	ENST00000681189.1 link	n.*23C>T		3_prime_UTR_variant	Exon 14 of 20			ENSP00000505973.1	A0A7P0TAF9
CUL4B	ENST00000681333.1 link	n.*2750C>T		3_prime_UTR_variant	Exon 11 of 17			ENSP00000505739.1	A0A7P0T9R8

Frequencies

GnomAD3 genomes

AF:

0.00113

AC:

126

AN:

111742

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000227

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000671

Gnomad ASJ

AF:

0.00339

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00438

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00847

Gnomad NFE

AF:

0.00162

Gnomad OTH

AF:

0.00201

GnomAD2 exomes

AF:

0.00173

AC:

307

AN:

177961

AF XY:

0.00208

show subpopulations

Gnomad AFR exome

AF:

0.000232

Gnomad AMR exome

AF:

0.000456

Gnomad ASJ exome

AF:

0.00343

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000192

Gnomad NFE exome

AF:

0.00208

Gnomad OTH exome

AF:

0.00229

GnomAD4 exome

AF:

0.00139

AC:

1453

AN:

1044703

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

522

AN XY:

318991

show subpopulations

African (AFR)

AF:

0.000158

AC:

AN:

25383

American (AMR)

AF:

0.000462

AC:

AN:

34656

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

18945

East Asian (EAS)

AF:

0.0000336

AC:

AN:

29802

South Asian (SAS)

AF:

0.00476

AC:

248

AN:

52067

European-Finnish (FIN)

AF:

0.000224

AC:

AN:

40210

Middle Eastern (MID)

AF:

0.00760

AC:

AN:

3682

European-Non Finnish (NFE)

AF:

0.00122

AC:

968

AN:

795661

Other (OTH)

AF:

0.00269

AC:

119

AN:

44297

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

121

161

201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00114

AC:

127

AN:

111794

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

34004

show subpopulations

African (AFR)

AF:

0.000227

AC:

AN:

30872

American (AMR)

AF:

0.000670

AC:

AN:

10446

Ashkenazi Jewish (ASJ)

AF:

0.00339

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3563

South Asian (SAS)

AF:

0.00476

AC:

AN:

2730

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5938

Middle Eastern (MID)

AF:

0.00930

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00162

AC:

AN:

53175

Other (OTH)

AF:

0.00198

AC:

AN:

1515

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00153

Hom.:

Bravo

AF:

0.00110

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jan 06, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 08, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

X-linked intellectual disability Cabezas type

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 13, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

May 15, 2014

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 06, 2017

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jul 27, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

CUL4B-related disorder

Benign:1

Jul 05, 2022

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

4.7

(source)

DANN

Benign

0.49

PhyloP100

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over