2-111150129-C-A

Position:

• chr2-111150129-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_138621.5(BCL2L11):​c.480C>A​(p.Asn160Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: BCL2L11 NM_138621.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.286

Genes affected

BCL2L11 (HGNC:994): (BCL2 like 11) The protein encoded by this gene belongs to the BCL-2 protein family. BCL-2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. The protein encoded by this gene contains a Bcl-2 homology domain 3 (BH3). It has been shown to interact with other members of the BCL-2 protein family and to act as an apoptotic activator. The expression of this gene can be induced by nerve growth factor (NGF), as well as by the forkhead transcription factor FKHR-L1, which suggests a role of this gene in neuronal and lymphocyte apoptosis. Transgenic studies of the mouse counterpart suggested that this gene functions as an essential initiator of apoptosis in thymocyte-negative selection. Several alternatively spliced transcript variants of this gene have been identified. [provided by RefSeq, Jun 2013]

MIR4435-2HG (HGNC:35163): (MIR4435-2 host gene)

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a mutagenesis_site Retains the ability to induce apoptosis. Abolishes interaction with BCL2; in isoform Bim-alpha3 and isoform BimS. No effect on interaction with BAX. (size 0) in uniprot entity B2L11_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCL2L11	NM_138621.5	c.480C>A	p.Asn160Lys	missense_variant	3/4	ENST00000393256.8	NP_619527.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCL2L11	ENST00000393256.8	c.480C>A	p.Asn160Lys	missense_variant	3/4	1	NM_138621.5	ENSP00000376943	P1
MIR4435-2HG	ENST00000645030.2	n.453-113207G>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2024

The c.480C>A (p.N160K) alteration is located in exon 3 (coding exon 2) of the BCL2L11 gene. This alteration results from a C to A substitution at nucleotide position 480, causing the asparagine (N) at amino acid position 160 to be replaced by a lysine (K). 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	0.94
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	.;.;.;.;.;D;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.97	.;L;.;L;.;L;.
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.1	D;.;.;.;.;D;.
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D;.;.;.;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;.
Polyphen		1.0	D;.;.;.;.;P;.
Vest4		0.92
MutPred		0.81		.;Gain of methylation at N160 (P = 0.0139);.;Gain of methylation at N160 (P = 0.0139);.;Gain of methylation at N160 (P = 0.0139);.;
MVP		0.29
MPC		0.34
ClinPred		0.99	D
GERP RS		-4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.82

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: chr2-111907706;