2-111123785-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_138621.5(BCL2L11):ā€‹c.40C>Gā€‹(p.Arg14Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000462 in 1,448,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.00023 ( 0 hom., cov: 33)
Exomes š‘“: 0.000025 ( 0 hom. )

Consequence

BCL2L11
NM_138621.5 missense

Scores

1
4
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0480
Variant links:
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)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.15667528).
BS2
High AC in GnomAd4 at 35 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BCL2L11NM_138621.5 linkuse as main transcriptc.40C>G p.Arg14Gly missense_variant 2/4 ENST00000393256.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BCL2L11ENST00000393256.8 linkuse as main transcriptc.40C>G p.Arg14Gly missense_variant 2/41 NM_138621.5 P1O43521-1
MIR4435-2HGENST00000645030.2 linkuse as main transcriptn.453-86863G>C intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.000230
AC:
35
AN:
152058
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00210
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000957
GnomAD4 exome
AF:
0.0000247
AC:
32
AN:
1296708
Hom.:
0
Cov.:
33
AF XY:
0.0000174
AC XY:
11
AN XY:
631280
show subpopulations
Gnomad4 AFR exome
AF:
0.0000354
Gnomad4 AMR exome
AF:
0.000672
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:
9.73e-7
Gnomad4 OTH exome
AF:
0.000265
GnomAD4 genome
AF:
0.000230
AC:
35
AN:
152058
Hom.:
0
Cov.:
33
AF XY:
0.000175
AC XY:
13
AN XY:
74250
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00210
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000957
Alfa
AF:
0.000285
Hom.:
0
Bravo
AF:
0.000620

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 07, 2024The c.40C>G (p.R14G) alteration is located in exon 2 (coding exon 1) of the BCL2L11 gene. This alteration results from a C to G substitution at nucleotide position 40, causing the arginine (R) at amino acid position 14 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
Benign
0.083
BayesDel_addAF
Benign
-0.058
T
BayesDel_noAF
Benign
-0.32
CADD
Benign
17
DANN
Uncertain
0.99
DEOGEN2
Benign
0.074
.;.;T;.;.;.;.;.;.;.;.;D;T;.;.;.;T
Eigen
Benign
-0.35
Eigen_PC
Benign
-0.30
FATHMM_MKL
Benign
0.29
N
LIST_S2
Uncertain
0.93
D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;D
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.16
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.68
T
MutationAssessor
Benign
0.20
.;N;.;N;N;N;N;N;N;N;N;N;.;N;N;N;.
MutationTaster
Benign
0.69
D;D;D;D;D;D
PrimateAI
Uncertain
0.63
T
PROVEAN
Pathogenic
-5.5
D;D;D;D;.;.;.;.;.;.;.;D;D;D;.;.;D
REVEL
Benign
0.22
Sift
Uncertain
0.024
D;D;D;D;.;.;.;.;.;.;.;D;D;D;.;.;D
Sift4G
Benign
0.068
T;D;D;T;T;D;T;T;T;T;D;T;T;D;.;.;D
Polyphen
0.88, 1.0, 0.40, 0.45
.;P;.;D;.;.;.;B;.;.;.;B;.;P;.;.;.
Vest4
0.28, 0.23, 0.27, 0.28, 0.31, 0.36, 0.31, 0.29, 0.24, 0.28, 0.30
MutPred
0.38
Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);Gain of loop (P = 0.0166);.;
MVP
0.25
MPC
0.18
ClinPred
0.99
D
GERP RS
-0.63
Varity_R
0.33
gMVP
0.18

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1041372390; hg19: chr2-111881362; API