rs200041771

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr14-23308865-G-A
• chr14-23308865-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004050.5(BCL2L2):​c.482G>A​(p.Arg161His) variant causes a missense change. The variant allele was found at a frequency of 0.000122 in 1,319,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 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. R161P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: BCL2L2 NM_004050.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.66
• Publications: 7 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010387719).

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>A	p.Arg161His	missense	Exon 4 of 4	NP_004041.2	Q92843-1
	BCL2L2-PABPN1	NM_001387340.1		c.482G>A	p.Arg161His	missense	Exon 4 of 10	NP_001374269.1
	BCL2L2	NM_001199839.2		c.482G>A	p.Arg161His	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>A	p.Arg161His	missense	Exon 4 of 4	ENSP00000250405.6	Q92843-1
	BCL2L2-PABPN1	ENST00000553781.5	TSL:2	c.432+666G>A		intron	N/A	ENSP00000451320.1	Q92843-2
	BCL2L2	ENST00000678311.1		c.482G>A	p.Arg161His	missense	Exon 4 of 4	ENSP00000504570.1	Q92843-1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152166 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000195 AC: 24 AN: 123114 AF XY: 0.0000912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000488

Gnomad ASJ exome AF: 0.00758

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000604

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000110 AC: 128 AN: 1167606 Hom.: 0 Cov.: 30 AF XY: 0.0000911 AC XY: 51 AN XY: 560044

African (AFR) AF: 0.0000400 AC: 1 AN: 24972

American (AMR) AF: 0.000456 AC: 8 AN: 17540

Ashkenazi Jewish (ASJ) AF: 0.00414 AC: 64 AN: 15450

East Asian (EAS) AF: 0.0000327 AC: 1 AN: 30586

South Asian (SAS) AF: 0.00 AC: 0 AN: 28134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41346

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4644

European-Non Finnish (NFE) AF: 0.0000334 AC: 32 AN: 958268

Other (OTH) AF: 0.000471 AC: 22 AN: 46666

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152284 Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 12 AN XY: 74468

African (AFR) AF: 0.0000241 AC: 1 AN: 41550

American (AMR) AF: 0.000523 AC: 8 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000258 Hom.: 0

Bravo AF: 0.000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000165 AC: 19

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	0.14
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.057	T
Eigen	Benign	0.091
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		5.7
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.27
Sift	Benign	0.081	T
Sift4G	Uncertain	0.055	T
Polyphen		0.99	D
Vest4		0.39
MVP		0.66
MPC		0.82
ClinPred		0.11	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.25
Mutation Taster		=81/19	polymorphism

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: rs200041771; hg19: chr14-23778074; COSMIC: COSV51635501; COSMIC: COSV51635501;