chr19-49666041-G-C

Position:

• chr19-49666041-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001282520.1(BCL2L12):​c.218G>C​(p.Arg73Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,409,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BCL2L12 NM_001282520.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.317

Genes affected

BCL2L12 (HGNC:13787): (BCL2 like 12) This gene encodes a member of a family of proteins containing a Bcl-2 homology domain 2 (BH2). The encoded protein is an anti-apoptotic factor that acts as an inhibitor of caspases 3 and 7 in the cytoplasm. In the nucleus, it binds to the p53 tumor suppressor protein, preventing its association with target genes. Overexpression of this gene has been detected in a number of different cancers. There is a pseudogene for this gene on chromosome 3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

BCL2L12 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.104417205).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCL2L12	NM_138639.2	c.-35G>C		5_prime_UTR_variant	1/7	ENST00000246784.8	NP_619580.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BCL2L12	ENST00000246784	c.-35G>C		5_prime_UTR_variant	1/7	1	NM_138639.2	ENSP00000246784.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1409328 Hom.: 0 Cov.: 32 AF XY: 0.00000144 AC XY: 1 AN XY: 696262

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000185

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Oct 25, 2022

The c.218G>C (p.R73T) alteration is located in exon 1 (coding exon 1) of the BCL2L12 gene. This alteration results from a G to C substitution at nucleotide position 218, causing the arginine (R) at amino acid position 73 to be replaced by a threonine (T). 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	Benign	0.14
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.9
DANN	Benign	0.71
DEOGEN2	Benign	0.041	T;T;T;T;.;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.00030	N
LIST_S2	Benign	0.47	T;T;T;T;T;.
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.10	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;.;.;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.19	.;.;.;.;N;N
REVEL	Benign	0.13
Sift	Benign	0.18	.;.;.;.;T;T
Sift4G	Benign	0.32	T;T;T;T;T;T
Polyphen		0.65	P;.;.;.;.;P
Vest4		0.072
MutPred		0.39		Gain of phosphorylation at R73 (P = 0.0223);Gain of phosphorylation at R73 (P = 0.0223);Gain of phosphorylation at R73 (P = 0.0223);Gain of phosphorylation at R73 (P = 0.0223);Gain of phosphorylation at R73 (P = 0.0223);Gain of phosphorylation at R73 (P = 0.0223);
MVP		0.46
MPC		0.26
ClinPred		0.13	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.031
gMVP		0.094

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2081733319; hg19: chr19-50169298;