2-60452670-G-GA

Position:

• chr2-60452670-G-GA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The ENST00000358510.6(BCL11A):​c.2281-5_2281-4insT variant causes a splice region, splice polypyrimidine tract, intron change. The variant allele was found at a frequency of 0.00196 in 1,610,670 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (4 hom.)
• Consequence: BCL11A ENST00000358510.6 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.15

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 2-60452670-G-GA is Benign according to our data. Variant chr2-60452670-G-GA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 992483.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00149 (227/152226) while in subpopulation NFE AF= 0.00293 (199/68016). AF 95% confidence interval is 0.00259. There are 0 homozygotes in gnomad4. There are 98 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 227 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCL11A	NM_001363864.1	c.2281-5_2281-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
BCL11A	NM_001405708.1	c.*3-5_*3-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
BCL11A	NM_001405710.1	c.2383-5_2383-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCL11A	ENST00000356842.9	c.2231-5_2231-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
BCL11A	ENST00000358510.6	c.2281-5_2281-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
BCL11A	ENST00000359629.10	c.631-5_631-4insT		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.00149 AC: 227 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000387

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00293

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00144 AC: 361 AN: 250366 Hom.: 0 AF XY: 0.00146 AC XY: 197 AN XY: 135388

Gnomad AFR exome AF: 0.000743

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000654

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00269

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00200 AC: 2923 AN: 1458444 Hom.: 4 Cov.: 29 AF XY: 0.00199 AC XY: 1446 AN XY: 725762

Gnomad4 AFR exome AF: 0.000569

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00102

Gnomad4 FIN exome AF: 0.000431

Gnomad4 NFE exome AF: 0.00241

Gnomad4 OTH exome AF: 0.00153

GnomAD4 genome AF: 0.00149 AC: 227 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74450

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00293

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00195 Hom.: 0

Bravo AF: 0.00143

EpiCase AF: 0.00294

EpiControl AF: 0.00249

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Dias-Logan syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

BCL11A NM_138559.1 intron 4A c.631-5dup: This variant has not been reported in the literature but is present in 0.2% (332/128478) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/2-60679805-G-GA?dataset=gnomad_r2_1). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is a single nucleotide intronic duplication variant with no predicted change in the amino acid sequence. Splice prediction tools suggest that this variant may not affect splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

BCL11A: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs113307140; hg19: chr2-60679805;