12-12094858-C-G

Position:

• chr12-12094858-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_138723.2(BCL2L14):​c.873C>G​(p.Asn291Lys) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BCL2L14 NM_138723.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.486

Genes affected

BCL2L14 (HGNC:16657): (BCL2 like 14) The protein encoded by this gene belongs to the BCL2 protein family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. Overexpression of this gene has been shown to induce apoptosis in cells. Three alternatively spliced transcript variants encoding two distinct isoforms have been reported for this gene. [provided by RefSeq, May 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCL2L14	NM_138723.2	c.873C>G	p.Asn291Lys	missense_variant	5/6	ENST00000308721.9	NP_620049.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCL2L14	ENST00000308721.9	c.873C>G	p.Asn291Lys	missense_variant	5/6	1	NM_138723.2	ENSP00000309132	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 05, 2023

The c.873C>G (p.N291K) alteration is located in exon 5 (coding exon 4) of the BCL2L14 gene. This alteration results from a C to G substitution at nucleotide position 873, causing the asparagine (N) at amino acid position 291 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;T;T;T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.64	D
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.0	M;.;M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.6	.;.;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0040	.;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.90
MutPred		0.60		Gain of catalytic residue at N291 (P = 0.0017);.;Gain of catalytic residue at N291 (P = 0.0017);Gain of catalytic residue at N291 (P = 0.0017);
MVP		0.45
MPC		0.60
ClinPred		0.99	D
GERP RS		1.8
Varity_R		0.42
gMVP		0.68

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-12247792;