NM_138576.4:c.2662A>G

Variant names:

• chr14-99174174-T-C
• NM_138576.4:c.2662A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138576.4(BCL11B):​c.2662A>G​(p.Ile888Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. I888M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCL11B NM_138576.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.18
• Publications: 0 publications found

Genes affected

BCL11B (HGNC:13222): (BCL11 transcription factor B) This gene encodes a C2H2-type zinc finger protein and is closely related to BCL11A, a gene whose translocation may be associated with B-cell malignancies. Although the specific function of this gene has not been determined, the encoded protein is known to be a transcriptional repressor, and is regulated by the NURD nucleosome remodeling and histone deacetylase complex. Four alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Aug 2013]

BCL11B Gene-Disease associations (from GenCC):

• intellectual developmental disorder with speech delay, dysmorphic facies, and t-cell abnormalities

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Illumina, ClinGen, G2P
• immunodeficiency 49

  Inheritance: AD, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18501478).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138576.4. 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
	BCL11B	NM_138576.4	MANE Select	c.2662A>G	p.Ile888Val	missense	Exon 4 of 4	NP_612808.1	Q9C0K0-1
	BCL11B	NM_001282237.2		c.2659A>G	p.Ile887Val	missense	Exon 4 of 4	NP_001269166.1
	BCL11B	NM_022898.3		c.2449A>G	p.Ile817Val	missense	Exon 3 of 3	NP_075049.1	Q9C0K0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCL11B	ENST00000357195.8	TSL:1 MANE Select	c.2662A>G	p.Ile888Val	missense	Exon 4 of 4	ENSP00000349723.3	Q9C0K0-1
	BCL11B	ENST00000345514.2	TSL:1	c.2449A>G	p.Ile817Val	missense	Exon 3 of 3	ENSP00000280435.6	Q9C0K0-2
	BCL11B	ENST00000443726.2	TSL:5	c.2080A>G	p.Ile694Val	missense	Exon 2 of 2	ENSP00000387419.2	D3YTK1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.0050
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.28	N
PhyloP100		5.2
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.093
Sift	Benign	0.098	T
Sift4G	Benign	0.37	T
Polyphen		0.42	B
Vest4		0.20
MutPred		0.28		Gain of ubiquitination at K887 (P = 0.0823)
MVP		0.35
MPC		1.1
ClinPred		0.72	D
GERP RS		4.9
Varity_R		0.11
gMVP		0.50
Mutation Taster		=92/8	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

hg19: chr14-99640511;