chr2-60461136-G-GCCA

Variant names:

• chr2-60461136-G-GCCA
• rs886037867
• NM_022893.4:c.1775_1776insTGG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The ENST00000642384.2(BCL11A):​c.1775_1776insTGG​(p.Gly592dup) variant causes a disruptive inframe insertion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. G592G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BCL11A ENST00000642384.2 disruptive_inframe_insertion
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.24
• Publications: 0 publications found

Genes affected

BCL11A (HGNC:13221): (BCL11 transcription factor A) This gene encodes a C2H2 type zinc-finger protein by its similarity to the mouse Bcl11a/Evi9 protein. The corresponding mouse gene is a common site of retroviral integration in myeloid leukemia, and may function as a leukemia disease gene, in part, through its interaction with BCL6. During hematopoietic cell differentiation, this gene is down-regulated. It is possibly involved in lymphoma pathogenesis since translocations associated with B-cell malignancies also deregulates its expression. Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

BCL11A Gene-Disease associations (from GenCC):

• Dias-Logan syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Ambry Genetics, G2P, Illumina

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000642384.2. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 2-60461136-G-GCCA is Pathogenic according to our data. Variant chr2-60461136-G-GCCA is described in ClinVar as Pathogenic. ClinVar VariationId is 253304.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000642384.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCL11A	NM_022893.4	MANE Select	c.1775_1776insTGG	p.Gly592dup	disruptive_inframe_insertion	Exon 4 of 4	NP_075044.2
	BCL11A	NM_001405708.1		c.1775_1776insTGG	p.Gly592dup	disruptive_inframe_insertion	Exon 4 of 5	NP_001392637.1
	BCL11A	NM_001405709.1		c.1775_1776insTGG	p.Gly592dup	disruptive_inframe_insertion	Exon 5 of 5	NP_001392638.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCL11A	ENST00000642384.2	MANE Select	c.1775_1776insTGG	p.Gly592dup	disruptive_inframe_insertion	Exon 4 of 4	ENSP00000496168.1
	BCL11A	ENST00000335712.11	TSL:1	c.1673_1674insTGG	p.Gly558dup	disruptive_inframe_insertion	Exon 3 of 3	ENSP00000338774.7
	BCL11A	ENST00000358510.6	TSL:1	c.1673_1674insTGG	p.Gly558dup	disruptive_inframe_insertion	Exon 3 of 4	ENSP00000351307.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 69

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Dias-Logan syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.2
Mutation Taster		=71/29	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs886037867; hg19: chr2-60688271;