chr2-111123785-C-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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. 13/21 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
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

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

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>G	p.Arg14Gly	missense	Exon 2 of 4	NP_619527.1	O43521-1
	BCL2L11	NM_001204108.1		c.40C>G	p.Arg14Gly	missense	Exon 2 of 5	NP_001191037.1	O43521-8
	BCL2L11	NM_138622.4		c.40C>G	p.Arg14Gly	missense	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>G	p.Arg14Gly	missense	Exon 2 of 4	ENSP00000376943.2	O43521-1
	BCL2L11	ENST00000405953.6	TSL:1	c.40C>G	p.Arg14Gly	missense	Exon 2 of 4	ENSP00000384641.1	O43521-17
	BCL2L11	ENST00000361493.10	TSL:1	n.40C>G		non_coding_transcript_exon	Exon 1 of 4	ENSP00000354879.6	A0A0C4DH20

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

African (AFR) AF: 0.0000354 AC: 1 AN: 28288

American (AMR) AF: 0.000672 AC: 16 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: 0.000265 AC: 14 AN: 52926

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152058 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74250

African (AFR) AF: 0.0000242 AC: 1 AN: 41392

American (AMR) AF: 0.00210 AC: 32 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68000

Other (OTH) AF: 0.000957 AC: 2 AN: 2090

Alfa AF: 0.000285 Hom.: 0

Bravo AF: 0.000620

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.20	N
PhyloP100		-0.048
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.22
Sift	Uncertain	0.024	D
Sift4G	Benign	0.068	T
Polyphen		0.88	P
Vest4		0.28
MutPred		0.38		Gain of loop (P = 0.0166)
MVP		0.25
MPC		0.18
ClinPred		0.99	D
GERP RS		-0.63
PromoterAI		0.014	Neutral
Varity_R		0.33
gMVP		0.18
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs1041372390; hg19: chr2-111881362;