rs1556196865

Variant names:

• chrX-120536932-G-T
• rs1556196865
• NM_001079872.2:c.2041C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001079872.2(CUL4B):​c.2041C>A​(p.Pro681Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P681L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.4e-7 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: CUL4B NM_001079872.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.56
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36016858).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL4B	NM_001079872.2	c.2041C>A	p.Pro681Thr	missense_variant	Exon 15 of 20	ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4	c.2095C>A	p.Pro699Thr	missense_variant	Exon 17 of 22		NP_003579.3
CUL4B	NM_001330624.2	c.2056C>A	p.Pro686Thr	missense_variant	Exon 16 of 21		NP_001317553.1
CUL4B	NM_001369145.1	c.1507C>A	p.Pro503Thr	missense_variant	Exon 15 of 20		NP_001356074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.2041C>A	p.Pro681Thr	missense_variant	Exon 15 of 20	1	NM_001079872.2	ENSP00000360373.5
CUL4B	ENST00000681206.1	c.2155C>A	p.Pro719Thr	missense_variant	Exon 18 of 23			ENSP00000505480.1
CUL4B	ENST00000680673.1	c.2095C>A	p.Pro699Thr	missense_variant	Exon 17 of 22			ENSP00000505084.1
CUL4B	ENST00000681253.1	c.2095C>A	p.Pro699Thr	missense_variant	Exon 18 of 23			ENSP00000506259.1
CUL4B	ENST00000681652.1	c.2095C>A	p.Pro699Thr	missense_variant	Exon 20 of 25			ENSP00000505176.1
CUL4B	ENST00000336592.11	c.2056C>A	p.Pro686Thr	missense_variant	Exon 16 of 21	5		ENSP00000338919.6
CUL4B	ENST00000674137.11	c.2047C>A	p.Pro683Thr	missense_variant	Exon 15 of 20			ENSP00000501019.6
CUL4B	ENST00000681090.1	c.1948C>A	p.Pro650Thr	missense_variant	Exon 15 of 20			ENSP00000506288.1
CUL4B	ENST00000404115.8	c.2041C>A	p.Pro681Thr	missense_variant	Exon 15 of 19	1		ENSP00000384109.4
CUL4B	ENST00000679927.1	c.1696C>A	p.Pro566Thr	missense_variant	Exon 16 of 21			ENSP00000505603.1
CUL4B	ENST00000371323.3	c.1507C>A	p.Pro503Thr	missense_variant	Exon 15 of 20	5		ENSP00000360374.3
CUL4B	ENST00000680474.1	c.1483C>A	p.Pro495Thr	missense_variant	Exon 14 of 20			ENSP00000505562.1
CUL4B	ENST00000679844.1	c.1378C>A	p.Pro460Thr	missense_variant	Exon 13 of 18			ENSP00000505239.1
CUL4B	ENST00000673919.1	n.*1488C>A		non_coding_transcript_exon_variant	Exon 16 of 21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.1483C>A		non_coding_transcript_exon_variant	Exon 14 of 18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1250C>A		non_coding_transcript_exon_variant	Exon 17 of 22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1250C>A		non_coding_transcript_exon_variant	Exon 17 of 22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*957C>A		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1250C>A		non_coding_transcript_exon_variant	Exon 15 of 20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*207C>A		non_coding_transcript_exon_variant	Exon 15 of 20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*2934C>A		non_coding_transcript_exon_variant	Exon 12 of 17			ENSP00000505739.1
CUL4B	ENST00000681869.1	n.1483C>A		non_coding_transcript_exon_variant	Exon 14 of 17			ENSP00000505597.1
CUL4B	ENST00000681908.1	n.*213C>A		non_coding_transcript_exon_variant	Exon 15 of 20			ENSP00000505777.1
CUL4B	ENST00000673919.1	n.*1488C>A		3_prime_UTR_variant	Exon 16 of 21			ENSP00000500994.1
CUL4B	ENST00000679405.1	n.*1250C>A		3_prime_UTR_variant	Exon 17 of 22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1250C>A		3_prime_UTR_variant	Exon 17 of 22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*957C>A		3_prime_UTR_variant	Exon 13 of 18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1250C>A		3_prime_UTR_variant	Exon 15 of 20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*207C>A		3_prime_UTR_variant	Exon 15 of 20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*2934C>A		3_prime_UTR_variant	Exon 12 of 17			ENSP00000505739.1
CUL4B	ENST00000681908.1	n.*213C>A		3_prime_UTR_variant	Exon 15 of 20			ENSP00000505777.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.44e-7 AC: 1 AN: 1059427 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 331995

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000390 AC: 1 AN: 25637

American (AMR) AF: 0.00 AC: 0 AN: 35162

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19172

East Asian (EAS) AF: 0.00 AC: 0 AN: 30056

South Asian (SAS) AF: 0.00 AC: 0 AN: 53259

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4044

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 806969

Other (OTH) AF: 0.00 AC: 0 AN: 44822

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Aug 18, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	22
DANN	Benign	0.92
DEOGEN2	Uncertain	0.50	.;.;T
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.3	.;.;L
PhyloP100		2.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Benign	0.15
Sift	Benign	0.17	T;T;T
Sift4G	Benign	0.71	T;T;T
Polyphen		0.0010	B;.;B
Vest4		0.26
MutPred		0.45		.;.;Loss of catalytic residue at P698 (P = 0.0121);
MVP		0.83
MPC		1.7
ClinPred		0.68	D
GERP RS		2.9
Varity_R		0.46
gMVP		0.49
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1556196865; hg19: chrX-119670787;