14-23308149-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004050.5(BCL2L2):c.382G>T(p.Ala128Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BCL2L2 NM_004050.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04

Genes affected

BCL2L2 (HGNC:995): (BCL2 like 2) This gene encodes a member of the BCL-2 protein family. The proteins of this family form hetero- or homodimers and act as anti- and pro-apoptotic regulators. Expression of this gene in cells has been shown to contribute to reduced cell apoptosis under cytotoxic conditions. Studies of the related gene in mice indicated a role in the survival of NGF- and BDNF-dependent neurons. Mutation and knockout studies of the mouse gene demonstrated an essential role in adult spermatogenesis. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the neighboring downstream PABPN1 (poly(A) binding protein, nuclear 1) gene. [provided by RefSeq, Dec 2010]

BCL2L2-PABPN1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20328712).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCL2L2	NM_004050.5	c.382G>T	p.Ala128Ser	missense_variant	3/4	ENST00000250405.10
BCL2L2-PABPN1	NM_001387343.1	c.382G>T	p.Ala128Ser	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCL2L2	ENST00000250405.10	c.382G>T	p.Ala128Ser	missense_variant	3/4	1	NM_004050.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248644 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134826

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000894

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461336 Hom.: 0 Cov.: 35 AF XY: 0.00000413 AC XY: 3 AN XY: 726910

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000471 Hom.: 0

ExAC AF: 0.00000824 AC: 1

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

Aug 31, 2022

The c.382G>T (p.A128S) alteration is located in exon 3 (coding exon 1) of the BCL2L2-PABPN1 gene. This alteration results from a G to T substitution at nucleotide position 382, causing the alanine (A) at amino acid position 128 to be replaced by a serine (S). 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	0.079
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	21
Dann	Benign	0.88
DEOGEN2	Benign	0.037	T;.;.;.;.
Eigen	Benign	-0.071
Eigen_PC	Benign	0.00021
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.75	T;T;T;.;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.18	N;N;N;N;N
REVEL	Benign	0.021
Sift	Benign	0.25	T;T;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T
Polyphen		0.0	B;.;.;.;.
Vest4		0.071
MutPred		0.37		Gain of catalytic residue at M126 (P = 0.0012);Gain of catalytic residue at M126 (P = 0.0012);Gain of catalytic residue at M126 (P = 0.0012);Gain of catalytic residue at M126 (P = 0.0012);Gain of catalytic residue at M126 (P = 0.0012);
MVP		0.35
MPC		0.61
ClinPred		0.051	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.55

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: rs762044603; hg19: chr14-23777358;