chr2-60452593-C-G

Variant names:

• chr2-60452593-C-G
• rs768802721
• ENST00000358510.6:c.2354G>C

Variant summary

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

The NM_001405710.1(BCL11A):​c.2456G>C​(p.Arg819Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict 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. R819G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BCL11A NM_001405710.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.365
• 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), Illumina, ClinGen, PanelApp Australia, Ambry Genetics, G2P

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=0.13367239).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001405710.1. 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
	BCL11A	NM_001405710.1		c.2456G>C	p.Arg819Pro	missense	Exon 5 of 5	NP_001392639.1
	BCL11A	NM_001363864.1		c.2354G>C	p.Arg785Pro	missense	Exon 4 of 4	NP_001350793.1	A0A2U3TZJ5
	BCL11A	NM_001405716.1		c.2300G>C	p.Arg767Pro	missense	Exon 5 of 5	NP_001392645.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCL11A	ENST00000358510.6	TSL:1	c.2354G>C	p.Arg785Pro	missense	Exon 4 of 4	ENSP00000351307.5	A0A2U3TZJ5
	BCL11A	ENST00000359629.10	TSL:1	c.704G>C	p.Arg235Pro	missense	Exon 5 of 5	ENSP00000352648.5	Q9H165-3
	BCL11A	ENST00000356842.9	TSL:1	c.2304G>C	p.Ser768Ser	synonymous	Exon 5 of 5	ENSP00000349300.4	Q9H165-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461736 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727170

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111912

Other (OTH) AF: 0.00 AC: 0 AN: 60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

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	0.14
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	18
DANN	Benign	0.95
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.065
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.98	T
PhyloP100		0.36
PROVEAN	Benign	1.8	N
REVEL	Benign	0.068
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.051	T
Polyphen		0.0040	B
Vest4		0.21
MutPred		0.34		Loss of MoRF binding (P = 0.0402)
MVP		0.24
ClinPred		0.15	T
GERP RS		3.1
Mutation Taster		=78/22	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs768802721; hg19: chr2-60679728;