22-17683229-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_015367.4(BCL2L13):c.137T>C(p.Ile46Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000762 in 1,568,648 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I46R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0040 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (7 hom.)
• Consequence: BCL2L13 NM_015367.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.18

Genes affected

BCL2L13 (HGNC:17164): (BCL2 like 13) This gene encodes a mitochondrially-localized protein with conserved B-cell lymphoma 2 homology motifs. Overexpression of the encoded protein results in apoptosis. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027754903).
• BP6: Variant 22-17683229-T-C is Benign according to our data. Variant chr22-17683229-T-C is described in ClinVar as [Benign]. Clinvar id is 788925.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCL2L13	NM_015367.4	c.137T>C	p.Ile46Thr	missense_variant	3/7	ENST00000317582.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCL2L13	ENST00000317582.10	c.137T>C	p.Ile46Thr	missense_variant	3/7	1	NM_015367.4	A2

Frequencies

GnomAD3 genomes AF: 0.00401 AC: 610 AN: 152054 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000972 AC: 233 AN: 239676 Hom.: 1 AF XY: 0.000716 AC XY: 93 AN XY: 129862

Gnomad AFR exome AF: 0.0137

Gnomad AMR exome AF: 0.000416

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000108

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.00000905

Gnomad OTH exome AF: 0.000172

GnomAD4 exome AF: 0.000412 AC: 583 AN: 1416482 Hom.: 7 Cov.: 27 AF XY: 0.000337 AC XY: 238 AN XY: 706842

Gnomad4 AFR exome AF: 0.0145

Gnomad4 AMR exome AF: 0.000551

Gnomad4 ASJ exome AF: 0.0000388

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000966

Gnomad4 FIN exome AF: 0.0000376

Gnomad4 NFE exome AF: 0.00000928

Gnomad4 OTH exome AF: 0.00116

GnomAD4 genome AF: 0.00403 AC: 613 AN: 152166 Hom.: 4 Cov.: 32 AF XY: 0.00370 AC XY: 275 AN XY: 74384

Gnomad4 AFR AF: 0.0143

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000770 Hom.: 1190

ExAC AF: 0.00126 AC: 153

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 24, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.0010
Dann	Benign	0.37
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.022	N
MetaRNN	Benign	0.0028	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.34	N;.;.;.;.;N;N;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.64	N;.;.;.;.;N;N;N
REVEL	Benign	0.016
Sift	Benign	0.80	T;.;.;.;.;T;T;T
Sift4G	Benign	0.14	T;T;T;T;T;T;T;T
Polyphen		0.0	B;.;.;.;.;B;B;B
Vest4		0.013
MVP		0.030
MPC		0.15
ClinPred		0.00046	T
GERP RS		-2.1
Varity_R		0.025
gMVP		0.14

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: rs2587070; hg19: chr22-18165995; COSMIC: COSV58225507;