chr19-49665941-C-T

Position:

• chr19-49665941-C-T

Variant summary

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

The NM_138639.2(BCL2L12):​c.-135C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,410 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BCL2L12 NM_138639.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.180

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=0.07592565).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BCL2L12	NM_138639.2	c.-135C>T		5_prime_UTR_premature_start_codon_gain_variant	1/7	ENST00000246784.8	NP_619580.2
BCL2L12	NM_138639.2	c.-135C>T		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.-135C>T		5_prime_UTR_premature_start_codon_gain_variant	1/7	1	NM_138639.2	ENSP00000246784.4
BCL2L12	ENST00000246784	c.-135C>T		5_prime_UTR_variant	1/7	1	NM_138639.2	ENSP00000246784.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461410 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726946

Gnomad4 AFR exome AF: 0.0000299

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000189

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Aug 17, 2022

The c.118C>T (p.R40C) alteration is located in exon 1 (coding exon 1) of the BCL2L12 gene. This alteration results from a C to T substitution at nucleotide position 118, causing the arginine (R) at amino acid position 40 to be replaced by a cysteine (C). 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	0.23
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.96
DEOGEN2	Benign	0.053	T;T;T;T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.00022	N
LIST_S2	Uncertain	0.86	D;D;D;D;D;.
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.076	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;.;.;.;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.6	.;.;.;.;N;N
REVEL	Benign	0.013
Sift	Benign	0.070	.;.;.;.;T;T
Sift4G	Benign	0.10	T;T;T;T;T;T
Polyphen		0.0020	B;.;.;.;.;B
Vest4		0.061
MutPred		0.41		Gain of catalytic residue at W41 (P = 8e-04);Gain of catalytic residue at W41 (P = 8e-04);Gain of catalytic residue at W41 (P = 8e-04);Gain of catalytic residue at W41 (P = 8e-04);Gain of catalytic residue at W41 (P = 8e-04);Gain of catalytic residue at W41 (P = 8e-04);
MVP		0.31
MPC		0.40
ClinPred		0.11	T
GERP RS		-0.19
Varity_R		0.12
gMVP		0.096

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

LitVar

Other links and lift over

dbSNP: rs2081722999; hg19: chr19-50169198;