chr18-63318269-A-G

Variant names:

• chr18-63318269-A-G
• NM_000633.3:c.398T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000633.3(BCL2):​c.398T>C​(p.Val133Ala) 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. Variant has been reported in ClinVar as (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCL2 NM_000633.3 missense
• Clinical Significance: Other O:1
• Conservation: PhyloP100: 9.14
• Publications: 1 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934

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.398T>C	p.Val133Ala	missense	Exon 2 of 3	NP_000624.2	P10415-1
	BCL2	NM_000657.3		c.398T>C	p.Val133Ala	missense	Exon 2 of 2	NP_000648.2	P10415-2
	BCL2	NM_001438935.1		c.398T>C	p.Val133Ala	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.398T>C	p.Val133Ala	missense	Exon 2 of 3	ENSP00000329623.3	P10415-1
	BCL2	ENST00000398117.1	TSL:1	c.398T>C	p.Val133Ala	missense	Exon 1 of 2	ENSP00000381185.1	P10415-1
	BCL2	ENST00000589955.2	TSL:6	c.398T>C	p.Val133Ala	missense	Exon 1 of 1	ENSP00000466417.1	P10415-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Other

Revision:

Pathogenic	VUS	Benign	Condition
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.91	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		9.1
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.83		Gain of phosphorylation at T132 (P = 0.1757)
MVP		0.84
MPC		2.2
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.96
gMVP		0.98
Mutation Taster		=24/76	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

hg19: chr18-60985502;