Genetic Variant CUL4B:p.Ser125_Ser126dup (chrX-120560261-T-TGAGGAG) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP3

The NM_001079872.2(CUL4B):c.372_377dupCTCCTC(p.Ser125_Ser126dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.00000901 in 111,015 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S126S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Consequence

CUL4B
NM_001079872.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP3

Nonframeshift variant in repetitive region in NM_001079872.2

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.372_377dupCTCCTC	p.Ser125_Ser126dup	disruptive_inframe_insertion	Exon 1 of 20	NP_001073341.1
CUL4B	NM_003588.4		c.426_431dupCTCCTC	p.Ser143_Ser144dup	disruptive_inframe_insertion	Exon 3 of 22	NP_003579.3
CUL4B	NM_001330624.2		c.387_392dupCTCCTC	p.Ser130_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.372_377dupCTCCTC	p.Ser125_Ser126dup	disruptive_inframe_insertion	Exon 1 of 20	ENSP00000360373.5
CUL4B	ENST00000681206.1		c.387_392dupCTCCTC	p.Ser130_Ser131dup	disruptive_inframe_insertion	Exon 2 of 23	ENSP00000505480.1
CUL4B	ENST00000680673.1		c.426_431dupCTCCTC	p.Ser143_Ser144dup	disruptive_inframe_insertion	Exon 3 of 22	ENSP00000505084.1

Frequencies

GnomAD3 genomes

AF:

0.00000901

AC:

AN:

111015

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000170

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000901

AC:

AN:

111015

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33341

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30539

American (AMR)

AF:

0.00

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:

0.000170

AC:

AN:

5898

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52899

Other (OTH)

AF:

0.00

AC:

AN:

1493

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.8

Splicing

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

Publications

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X-120560261-TGAGGAGGAG-TGAGGAGGAGGAGGAG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over