rs888230251

Variant names:

• chr14-99174415-G-C
• rs888230251
• NM_138576.4:c.2421C>G

Your query was ambiguous. Multiple possible variants found:

• chr14-99174415-G-C
• chr14-99174415-G-A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_138576.4(BCL11B):​c.2421C>G​(p.Asn807Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCL11B NM_138576.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.73
• Publications: 5 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: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-99174415-G-C is Pathogenic according to our data. Variant chr14-99174415-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 560174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2421C>G	p.Asn807Lys	missense	Exon 4 of 4	NP_612808.1	Q9C0K0-1
	BCL11B	NM_001282237.2		c.2418C>G	p.Asn806Lys	missense	Exon 4 of 4	NP_001269166.1
	BCL11B	NM_022898.3		c.2208C>G	p.Asn736Lys	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.2421C>G	p.Asn807Lys	missense	Exon 4 of 4	ENSP00000349723.3	Q9C0K0-1
	BCL11B	ENST00000345514.2	TSL:1	c.2208C>G	p.Asn736Lys	missense	Exon 3 of 3	ENSP00000280435.6	Q9C0K0-2
	BCL11B	ENST00000443726.2	TSL:5	c.1839C>G	p.Asn613Lys	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: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Intellectual developmental disorder with speech delay, dysmorphic facies, and t-cell abnormalities (3)
1	-	-	Immunodeficiency 49 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
PhyloP100		7.7
Varity_R		0.79
gMVP		0.87
Mutation Taster		=9/91	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs888230251; hg19: chr14-99640752;