Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3BP6_Very_StrongBS2

The NM_001079872.2(CUL4B):c.375_377dupCTC(p.Ser126dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.0000306 in 1,208,157 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S126S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.000028 ( 0 hom. 8 hem. )

Consequence

CUL4B
NM_001079872.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:1B:3

Conservation

PhyloP100: 4.84

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 -13 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001079872.2

BP6

Variant X-120560261-T-TGAG is Benign according to our data. Variant chrX-120560261-T-TGAG is described in ClinVar as Likely_benign. ClinVar VariationId is 420582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 2 XL gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CUL4B	NM_001079872.2	MANE Select	c.375_377dupCTC	p.Ser126dup	disruptive_inframe_insertion	Exon 1 of 20	NP_001073341.1
CUL4B	NM_003588.4		c.429_431dupCTC	p.Ser144dup	disruptive_inframe_insertion	Exon 3 of 22	NP_003579.3
CUL4B	NM_001330624.2		c.390_392dupCTC	p.Ser131dup	disruptive_inframe_insertion	Exon 2 of 21	NP_001317553.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CUL4B	ENST00000371322.11	TSL:1 MANE Select	c.375_377dupCTC	p.Ser126dup	disruptive_inframe_insertion	Exon 1 of 20	ENSP00000360373.5
CUL4B	ENST00000681206.1		c.390_392dupCTC	p.Ser131dup	disruptive_inframe_insertion	Exon 2 of 23	ENSP00000505480.1
CUL4B	ENST00000680673.1		c.429_431dupCTC	p.Ser144dup	disruptive_inframe_insertion	Exon 3 of 22	ENSP00000505084.1

Frequencies

GnomAD3 genomes

AF:

0.0000540

AC:

AN:

111014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000982

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000958

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000378

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000404

AC:

AN:

173145

AF XY:

0.0000325

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.000139

Gnomad EAS exome

AF:

0.000154

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000128

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000283

AC:

AN:

1097143

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

362877

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26382

American (AMR)

AF:

0.0000852

AC:

AN:

35195

Ashkenazi Jewish (ASJ)

AF:

0.0000516

AC:

AN:

19372

East Asian (EAS)

AF:

0.000132

AC:

AN:

30195

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54096

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40449

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.0000262

AC:

AN:

841257

Other (OTH)

AF:

0.00

AC:

AN:

46064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.0000540

AC:

AN:

111014

Hom.:

Cov.:

AF XY:

0.0000600

AC XY:

AN XY:

33340

show subpopulations

African (AFR)

AF:

0.0000982

AC:

AN:

30539

American (AMR)

AF:

0.0000958

AC:

AN:

10437

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2637

East Asian (EAS)

AF:

0.00

AC:

AN:

3537

South Asian (SAS)

AF:

0.00

AC:

AN:

2654

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5898

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000378

AC:

AN:

52898

Other (OTH)

AF:

0.00

AC:

AN:

1493

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000434

Hom.:

Bravo

AF:

0.0000378

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

CUL4B-related disorder (1)

Inborn genetic diseases (1)

not specified (1)

X-linked intellectual disability Cabezas type (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.8

Mutation Taster

=87/13

polymorphism

(source)

Splicing

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

Publications

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X-120560261-TGAGGAGGAG-TGAGGAGGAGGAG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over