NM_001079872.2:c.1857C>T

Variant names:

• chrX-120538205-G-A
• rs148700620
• NM_001079872.2:c.1857C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.73
• Publications: 1 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL4B	NM_001079872.2	MANE Select	c.1857C>T	p.Cys619Cys	synonymous	Exon 14 of 20	NP_001073341.1	Q13620-1
	CUL4B	NM_003588.4		c.1911C>T	p.Cys637Cys	synonymous	Exon 16 of 22	NP_003579.3
	CUL4B	NM_001330624.2		c.1872C>T	p.Cys624Cys	synonymous	Exon 15 of 21	NP_001317553.1	K4DI93

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL4B	ENST00000371322.11	TSL:1 MANE Select	c.1857C>T	p.Cys619Cys	synonymous	Exon 14 of 20	ENSP00000360373.5	Q13620-1
	CUL4B	ENST00000681206.1		c.1971C>T	p.Cys657Cys	synonymous	Exon 17 of 23	ENSP00000505480.1	A0A7P0T954
	CUL4B	ENST00000680673.1		c.1911C>T	p.Cys637Cys	synonymous	Exon 16 of 22	ENSP00000505084.1	Q13620-2

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 126 AN: 111742 Hom.: 0 Cov.: 23

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

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.: 0 Cov.: 23 AF XY: 0.00164 AC XY: 522 AN XY: 318991

African (AFR) AF: 0.000158 AC: 4 AN: 25383

American (AMR) AF: 0.000462 AC: 16 AN: 34656

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 60 AN: 18945

East Asian (EAS) AF: 0.0000336 AC: 1 AN: 29802

South Asian (SAS) AF: 0.00476 AC: 248 AN: 52067

European-Finnish (FIN) AF: 0.000224 AC: 9 AN: 40210

Middle Eastern (MID) AF: 0.00760 AC: 28 AN: 3682

European-Non Finnish (NFE) AF: 0.00122 AC: 968 AN: 795661

Other (OTH) AF: 0.00269 AC: 119 AN: 44297

GnomAD4 genome AF: 0.00114 AC: 127 AN: 111794 Hom.: 0 Cov.: 23 AF XY: 0.00106 AC XY: 36 AN XY: 34004

African (AFR) AF: 0.000227 AC: 7 AN: 30872

American (AMR) AF: 0.000670 AC: 7 AN: 10446

Ashkenazi Jewish (ASJ) AF: 0.00339 AC: 9 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3563

South Asian (SAS) AF: 0.00476 AC: 13 AN: 2730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5938

Middle Eastern (MID) AF: 0.00930 AC: 2 AN: 215

European-Non Finnish (NFE) AF: 0.00162 AC: 86 AN: 53175

Other (OTH) AF: 0.00198 AC: 3 AN: 1515

Alfa AF: 0.00153 Hom.: 10

Bravo AF: 0.00110

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	X-linked intellectual disability Cabezas type (3)
-	-	2	not specified (2)
-	-	1	CUL4B-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	4.7
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)

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

Other links and lift over

dbSNP: rs148700620; hg19: chrX-119672060; COSMIC: COSV100340271;