2-111123785-C-T

Variant names:

• chr2-111123785-C-T
• rs1041372390
• NM_138621.5:c.40C>T

Variant summary

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

The NM_138621.5(BCL2L11):​c.40C>T​(p.Arg14*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000771 in 1,296,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: BCL2L11 NM_138621.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0480
• Publications: 0 publications found

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)

ENSG00000293584 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138621.5. 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
	BCL2L11	NM_138621.5	MANE Select	c.40C>T	p.Arg14*	stop_gained	Exon 2 of 4	NP_619527.1	O43521-1
	BCL2L11	NM_001204108.1		c.40C>T	p.Arg14*	stop_gained	Exon 2 of 5	NP_001191037.1	O43521-8
	BCL2L11	NM_138622.4		c.40C>T	p.Arg14*	stop_gained	Exon 2 of 5	NP_619528.1	O43521-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCL2L11	ENST00000393256.8	TSL:1 MANE Select	c.40C>T	p.Arg14*	stop_gained	Exon 2 of 4	ENSP00000376943.2	O43521-1
	BCL2L11	ENST00000405953.6	TSL:1	c.40C>T	p.Arg14*	stop_gained	Exon 2 of 4	ENSP00000384641.1	O43521-17
	BCL2L11	ENST00000361493.10	TSL:1	n.40C>T		non_coding_transcript_exon	Exon 1 of 4	ENSP00000354879.6	A0A0C4DH20

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.71e-7 AC: 1 AN: 1296708 Hom.: 0 Cov.: 33 AF XY: 0.00000158 AC XY: 1 AN XY: 631280

⚠️ 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: 28288

American (AMR) AF: 0.00 AC: 0 AN: 23800

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18224

East Asian (EAS) AF: 0.00 AC: 0 AN: 35206

South Asian (SAS) AF: 0.00 AC: 0 AN: 57432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5102

European-Non Finnish (NFE) AF: 9.73e-7 AC: 1 AN: 1028216

Other (OTH) AF: 0.00 AC: 0 AN: 52926

⚠️ 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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.081
FATHMM_MKL	Benign	0.31	N
PhyloP100		-0.048
Vest4		0.90
GERP RS		-0.63
PromoterAI		-0.045	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=12/188	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1041372390; hg19: chr2-111881362;