18-63318540-C-T

Variant names:

• chr18-63318540-C-T
• rs1800477
• NM_000633.3:c.127G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000633.3(BCL2):​c.127G>A​(p.Ala43Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00711 in 1,584,596 control chromosomes in the GnomAD database, including 501 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0068 (51 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (450 hom.)
• Consequence: BCL2 NM_000633.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0250
• Publications: 39 publications found

Genes affected

BCL2 (HGNC:990): (BCL2 apoptosis regulator) This gene encodes an integral outer mitochondrial membrane protein that blocks the apoptotic death of some cells such as lymphocytes. Constitutive expression of BCL2, such as in the case of translocation of BCL2 to Ig heavy chain locus, is thought to be the cause of follicular lymphoma. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017367601).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0828 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000633.3. 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
	BCL2	NM_000633.3	MANE Select	c.127G>A	p.Ala43Thr	missense	Exon 2 of 3	NP_000624.2	P10415-1
	BCL2	NM_000657.3		c.127G>A	p.Ala43Thr	missense	Exon 2 of 2	NP_000648.2	P10415-2
	BCL2	NM_001438935.1		c.127G>A	p.Ala43Thr	missense	Exon 2 of 3	NP_001425864.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCL2	ENST00000333681.5	TSL:1 MANE Select	c.127G>A	p.Ala43Thr	missense	Exon 2 of 3	ENSP00000329623.3	P10415-1
	BCL2	ENST00000398117.1	TSL:1	c.127G>A	p.Ala43Thr	missense	Exon 1 of 2	ENSP00000381185.1	P10415-1
	BCL2	ENST00000589955.2	TSL:6	c.127G>A	p.Ala43Thr	missense	Exon 1 of 1	ENSP00000466417.1	P10415-2

Frequencies

GnomAD3 genomes AF: 0.00672 AC: 1022 AN: 152124 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0895

Gnomad SAS AF: 0.0865

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.0178 AC: 3838 AN: 215822 AF XY: 0.0206

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.000488

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0979

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000305

Gnomad OTH exome AF: 0.00889

GnomAD4 exome AF: 0.00714 AC: 10228 AN: 1432356 Hom.: 450 Cov.: 34 AF XY: 0.00929 AC XY: 6620 AN XY: 712880

African (AFR) AF: 0.000359 AC: 11 AN: 30674

American (AMR) AF: 0.000556 AC: 23 AN: 41360

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25226

East Asian (EAS) AF: 0.0681 AC: 2486 AN: 36522

South Asian (SAS) AF: 0.0790 AC: 6699 AN: 84782

European-Finnish (FIN) AF: 0.0000210 AC: 1 AN: 47678

Middle Eastern (MID) AF: 0.00319 AC: 18 AN: 5646

European-Non Finnish (NFE) AF: 0.000211 AC: 232 AN: 1101256

Other (OTH) AF: 0.0128 AC: 758 AN: 59212

GnomAD4 genome AF: 0.00679 AC: 1033 AN: 152240 Hom.: 51 Cov.: 32 AF XY: 0.00848 AC XY: 631 AN XY: 74434

African (AFR) AF: 0.00149 AC: 62 AN: 41564

American (AMR) AF: 0.00294 AC: 45 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0896 AC: 462 AN: 5158

South Asian (SAS) AF: 0.0868 AC: 419 AN: 4826

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 67988

Other (OTH) AF: 0.0128 AC: 27 AN: 2112

Alfa AF: 0.00145 Hom.: 2

Bravo AF: 0.00505

ESP6500AA AF: 0.00160 AC: 6

ESP6500EA AF: 0.000248 AC: 2

ExAC AF: 0.0178 AC: 2140

Asia WGS AF: 0.0890 AC: 308 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	9.4
DANN	Uncertain	0.98
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.97	L
PhyloP100		-0.025
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.064
Sift	Benign	0.69	T
Sift4G	Benign	0.67	T
Polyphen		0.99	D
Vest4		0.018
MPC		0.85
ClinPred		0.0036	T
GERP RS		1.6
PromoterAI		0.030	Neutral
Varity_R		0.028
gMVP		0.35
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1800477; hg19: chr18-60985773; COSMIC: COSV61380124;