2-60460751-T-C

Variant names:

• chr2-60460751-T-C
• NM_022893.4:c.2161A>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_022893.4(BCL11A):​c.2161A>G​(p.Ser721Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCL11A NM_022893.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.27

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the BCL11A gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Gene score misZ: 3.835 (above the threshold of 3.09). Trascript score misZ: 3.6065 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability, autosomal dominant 40, Dias-Logan syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3163154).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BCL11A	NM_022893.4	c.2161A>G	p.Ser721Gly	missense_variant	Exon 4 of 4	ENST00000642384.2	NP_075044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCL11A	ENST00000642384.2	c.2161A>G	p.Ser721Gly	missense_variant	Exon 4 of 4		NM_022893.4	ENSP00000496168.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 20, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2161A>G (p.S721G) alteration is located in exon 4 (coding exon 4) of the BCL11A gene. This alteration results from a A to G substitution at nucleotide position 2161, causing the serine (S) at amino acid position 721 to be replaced by a glycine (G). 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	0.62
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	32
DANN	Benign	0.97
DEOGEN2	Benign	0.29	.;.;T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;.;M;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.2	N;D;.;D
REVEL	Benign	0.17
Sift	Uncertain	0.0020	D;D;.;D
Sift4G	Uncertain	0.0070	D;T;.;.
Polyphen		1.0, 0.0030	.;.;D;B
Vest4		0.67
MutPred		0.25		Loss of phosphorylation at S721 (P = 0.0053);.;Loss of phosphorylation at S721 (P = 0.0053);.;
MVP		0.61
ClinPred		0.87	D
GERP RS		5.9
Varity_R		0.32
gMVP		0.75

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-60687886;