2-111123785-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_138621.5(BCL2L11):c.40C>G(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 (★).

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: BCL2L11 NM_138621.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0480

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 Likely_benign. Variant got -6 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCL2L11	NM_138621.5	c.40C>G	p.Arg14Gly	missense_variant	2/4	ENST00000393256.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCL2L11	ENST00000393256.8	c.40C>G	p.Arg14Gly	missense_variant	2/4	1	NM_138621.5	P1
MIR4435-2HG	ENST00000645030.2	n.453-86863G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000230 AC: 35 AN: 152058 Hom.: 0 Cov.: 33

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

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

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

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2022

The 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
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
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

Other links and lift over

dbSNP: rs1041372390; hg19: chr2-111881362;