NM_138578.3:c.674T>C

Variant names:

• chr20-31665977-A-G
• rs2122387594
• NM_138578.3:c.674T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_138578.3(BCL2L1):​c.674T>C​(p.Leu225Pro) variant causes a missense change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BCL2L1 NM_138578.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.03
• Publications: 0 publications found

Genes affected

BCL2L1 (HGNC:992): (BCL2 like 1) The protein encoded by this gene belongs to the BCL-2 protein family. BCL-2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. The proteins encoded by this gene are located at the outer mitochondrial membrane, and have been shown to regulate outer mitochondrial membrane channel (VDAC) opening. VDAC regulates mitochondrial membrane potential, and thus controls the production of reactive oxygen species and release of cytochrome C by mitochondria, both of which are the potent inducers of cell apoptosis. Alternative splicing results in multiple transcript variants encoding two different isoforms. The longer isoform acts as an apoptotic inhibitor and the shorter isoform acts as an apoptotic activator. [provided by RefSeq, Dec 2015]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138578.3. 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
	BCL2L1	NM_138578.3	MANE Select	c.674T>C	p.Leu225Pro	missense	Exon 3 of 3	NP_612815.1	Q07817-1
	BCL2L1	NM_001317919.2		c.674T>C	p.Leu225Pro	missense	Exon 3 of 3	NP_001304848.1	A0A0S2Z3C5
	BCL2L1	NM_001317920.2		c.674T>C	p.Leu225Pro	missense	Exon 3 of 3	NP_001304849.1	Q07817-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCL2L1	ENST00000307677.5	TSL:1 MANE Select	c.674T>C	p.Leu225Pro	missense	Exon 3 of 3	ENSP00000302564.4	Q07817-1
	BCL2L1	ENST00000376062.6	TSL:1	c.674T>C	p.Leu225Pro	missense	Exon 2 of 2	ENSP00000365230.2	Q07817-1
	BCL2L1	ENST00000450273.2	TSL:3	c.896T>C	p.Leu299Pro	missense	Exon 4 of 4	ENSP00000406203.2	Q5TE64

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.090	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	2.0	M
PhyloP100		7.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.84
MutPred		0.70		Loss of stability (P = 0.0464)
MVP		0.92
MPC		1.4
ClinPred		0.86	D
GERP RS		5.0
Varity_R		0.64
gMVP		0.96
Mutation Taster		=30/70	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: rs2122387594; hg19: chr20-30253780;