2-60546163-C-G

Position:

• chr2-60546163-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1 PP2 BS2

The NM_022893.4(BCL11A):​c.193G>C​(p.Glu65Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: BCL11A NM_022893.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM1: In a region_of_interest Required for nuclear body formation and for SUMO1 recruitment (size 209) in uniprot entity BC11A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_022893.4
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BCL11A. . Gene score misZ 3.835 (greater than the threshold 3.09). Trascript score misZ 3.6065 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal dominant 40, Dias-Logan syndrome.
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCL11A	NM_022893.4	c.193G>C	p.Glu65Gln	missense_variant	2/4	ENST00000642384.2	NP_075044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCL11A	ENST00000642384.2	c.193G>C	p.Glu65Gln	missense_variant	2/4		NM_022893.4	ENSP00000496168.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2022

The c.193G>C (p.E65Q) alteration is located in exon 2 (coding exon 2) of the BCL11A gene. This alteration results from a G to C substitution at nucleotide position 193, causing the glutamic acid (E) at amino acid position 65 to be replaced by a glutamine (Q). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	32
DANN	Benign	0.96
DEOGEN2	Benign	0.21	.;.;.;.;.;.;.;T;.;.;.;.;.;.;.
Eigen	Uncertain	0.63
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.2	.;L;L;.;.;.;.;L;L;.;.;.;L;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.9	.;N;N;.;.;.;N;.;N;.;.;.;.;.;.
REVEL	Benign	0.29
Sift	Benign	0.11	.;T;T;.;.;.;T;.;T;.;.;.;.;.;.
Sift4G	Uncertain	0.045	.;D;T;.;.;.;T;.;T;.;.;.;T;.;.
Polyphen		1.0, 0.60	.;.;D;.;.;.;.;D;P;.;.;.;.;.;.
Vest4		0.81, 0.59, 0.80, 0.82, 0.68
MutPred		0.43		Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);.;Gain of helix (P = 0.0325);.;Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);Gain of helix (P = 0.0325);.;Gain of helix (P = 0.0325);.;Gain of helix (P = 0.0325);.;Gain of helix (P = 0.0325);
MVP		0.67
ClinPred		0.81	D
GERP RS		5.8
Varity_R		0.30
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553353022; hg19: chr2-60773298;