rs2144321951

Variant names:

• chr18-63318209-A-G
• rs2144321951
• NM_000633.3:c.458T>C

Your query was ambiguous. Multiple possible variants found:

• chr18-63318209-A-G
• chr18-63318209-A-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000633.3(BCL2):​c.458T>C​(p.Phe153Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F153Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCL2 NM_000633.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.20
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969

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.458T>C	p.Phe153Ser	missense	Exon 2 of 3	NP_000624.2	P10415-1
	BCL2	NM_000657.3		c.458T>C	p.Phe153Ser	missense	Exon 2 of 2	NP_000648.2	P10415-2
	BCL2	NM_001438935.1		c.458T>C	p.Phe153Ser	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.458T>C	p.Phe153Ser	missense	Exon 2 of 3	ENSP00000329623.3	P10415-1
	BCL2	ENST00000398117.1	TSL:1	c.458T>C	p.Phe153Ser	missense	Exon 1 of 2	ENSP00000381185.1	P10415-1
	BCL2	ENST00000589955.2	TSL:6	c.458T>C	p.Phe153Ser	missense	Exon 1 of 1	ENSP00000466417.1	P10415-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		9.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.88		Gain of glycosylation at F153 (P = 0.0187)
MVP		0.90
MPC		2.6
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.99
gMVP		1.0
Mutation Taster		=9/91	disease causing

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: rs2144321951; hg19: chr18-60985442;