NM_004050.5:c.482G>C

Variant names:

• chr14-23308865-G-C
• rs200041771
• NM_004050.5:c.482G>C

Variant summary

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

The NM_004050.5(BCL2L2):​c.482G>C​(p.Arg161Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R161H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: BCL2L2 NM_004050.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.66
• Publications: 0 publications found

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:42959): (BCL2L2-PABPN1 readthrough) This locus represents naturally occurring read-through transcription between the neighboring BCL2L2 (BCL2-like 2) and PABPN1 (poly(A) binding protein, nuclear 1) genes on chromosome 14. The read-through transcript encodes a fusion protein that shares sequence identity with each individual gene product. [provided by RefSeq, Dec 2010]

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_004050.5. 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
	BCL2L2	NM_004050.5	MANE Select	c.482G>C	p.Arg161Pro	missense	Exon 4 of 4	NP_004041.2	Q92843-1
	BCL2L2-PABPN1	NM_001387340.1		c.482G>C	p.Arg161Pro	missense	Exon 4 of 10	NP_001374269.1
	BCL2L2	NM_001199839.2		c.482G>C	p.Arg161Pro	missense	Exon 4 of 4	NP_001186768.2	Q92843-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCL2L2	ENST00000250405.10	TSL:1 MANE Select	c.482G>C	p.Arg161Pro	missense	Exon 4 of 4	ENSP00000250405.6	Q92843-1
	BCL2L2-PABPN1	ENST00000553781.5	TSL:2	c.432+666G>C		intron	N/A	ENSP00000451320.1	Q92843-2
	BCL2L2	ENST00000678311.1		c.482G>C	p.Arg161Pro	missense	Exon 4 of 4	ENSP00000504570.1	Q92843-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

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	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Benign	0.030	T
Eigen	Benign	0.027
Eigen_PC	Benign	0.075
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.41	N
PhyloP100		5.7
PROVEAN	Benign	-0.92	N
REVEL	Uncertain	0.29
Sift	Benign	0.57	T
Sift4G	Uncertain	0.051	T
Polyphen		0.99	D
Vest4		0.66
MutPred		0.50		Gain of catalytic residue at N166 (P = 0)
MVP		0.49
MPC		1.5
ClinPred		0.93	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.63
gMVP		0.65
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs200041771; hg19: chr14-23778074;