18-63318489-C-T

Variant names:

• chr18-63318489-C-T
• rs2144324924
• NM_000633.3:c.178G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000633.3(BCL2):​c.178G>A​(p.Ala60Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BCL2 NM_000633.3 missense
• Clinical Significance: Other O:1
• Conservation: PhyloP100: 0.749
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12674206).

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.178G>A	p.Ala60Thr	missense	Exon 2 of 3	NP_000624.2	P10415-1
	BCL2	NM_000657.3		c.178G>A	p.Ala60Thr	missense	Exon 2 of 2	NP_000648.2	P10415-2
	BCL2	NM_001438935.1		c.178G>A	p.Ala60Thr	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.178G>A	p.Ala60Thr	missense	Exon 2 of 3	ENSP00000329623.3	P10415-1
	BCL2	ENST00000398117.1	TSL:1	c.178G>A	p.Ala60Thr	missense	Exon 1 of 2	ENSP00000381185.1	P10415-1
	BCL2	ENST00000589955.2	TSL:6	c.178G>A	p.Ala60Thr	missense	Exon 1 of 1	ENSP00000466417.1	P10415-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.37e-7 AC: 1 AN: 1356438 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 669428

African (AFR) AF: 0.00 AC: 0 AN: 28058

American (AMR) AF: 0.00 AC: 0 AN: 30076

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20784

East Asian (EAS) AF: 0.00 AC: 0 AN: 34568

South Asian (SAS) AF: 0.00 AC: 0 AN: 72212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4978

European-Non Finnish (NFE) AF: 9.33e-7 AC: 1 AN: 1071492

Other (OTH) AF: 0.00 AC: 0 AN: 56082

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Other

Revision:

Pathogenic	VUS	Benign	Condition
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.0091	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.75
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.11
Sift	Benign	0.25	T
Sift4G	Uncertain	0.049	D
Polyphen		0.18	B
Vest4		0.17
MutPred		0.21		Gain of glycosylation at A60 (P = 0.0017)
MVP		0.46
MPC		0.85
ClinPred		0.53	D
GERP RS		3.2
PromoterAI		0.013	Neutral
Varity_R		0.073
gMVP		0.27

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: rs2144324924; hg19: chr18-60985722; COSMIC: COSV61388556;