rs1801018

Positions:

• chr18-63318646-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_000633.3(BCL2):​c.21A>G​(p.Thr7=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.398 in 1,612,024 control chromosomes in the GnomAD database, including 135,183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.32 (9647 hom., cov: 32)
  • Exomes 𝑓: 0.41 (125536 hom.)
• Consequence: BCL2 NM_000633.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.699

Genes affected

BCL2 (HGNC:990): (BCL2 apoptosis regulator) This gene encodes an integral outer mitochondrial membrane protein that blocks the apoptotic death of some cells such as lymphocytes. Constitutive expression of BCL2, such as in the case of translocation of BCL2 to Ig heavy chain locus, is thought to be the cause of follicular lymphoma. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 18-63318646-T-C is Benign according to our data. Variant chr18-63318646-T-C is described in ClinVar as [Benign]. Clinvar id is 3060318.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.699 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BCL2	NM_000633.3	c.21A>G	p.Thr7=	synonymous_variant	2/3	ENST00000333681.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BCL2	ENST00000333681.5	c.21A>G	p.Thr7=	synonymous_variant	2/3	1	NM_000633.3	P1

Frequencies

GnomAD3 genomes AF: 0.318 AC: 48421 AN: 152080 Hom.: 9644 Cov.: 32

Gnomad AFR AF: 0.0808

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.391

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.457

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.434

Gnomad OTH AF: 0.354

GnomAD3 exomes AF: 0.372 AC: 91756 AN: 246918 Hom.: 18853 AF XY: 0.378 AC XY: 50836 AN XY: 134404

Gnomad AFR exome AF: 0.0754

Gnomad AMR exome AF: 0.415

Gnomad ASJ exome AF: 0.351

Gnomad EAS exome AF: 0.0968

Gnomad SAS exome AF: 0.365

Gnomad FIN exome AF: 0.459

Gnomad NFE exome AF: 0.427

Gnomad OTH exome AF: 0.403

GnomAD4 exome AF: 0.406 AC: 593323 AN: 1459826 Hom.: 125536 Cov.: 65 AF XY: 0.407 AC XY: 295512 AN XY: 726246

Gnomad4 AFR exome AF: 0.0680

Gnomad4 AMR exome AF: 0.414

Gnomad4 ASJ exome AF: 0.347

Gnomad4 EAS exome AF: 0.105

Gnomad4 SAS exome AF: 0.368

Gnomad4 FIN exome AF: 0.459

Gnomad4 NFE exome AF: 0.431

Gnomad4 OTH exome AF: 0.371

GnomAD4 genome AF: 0.318 AC: 48426 AN: 152198 Hom.: 9647 Cov.: 32 AF XY: 0.320 AC XY: 23836 AN XY: 74428

Gnomad4 AFR AF: 0.0805

Gnomad4 AMR AF: 0.391

Gnomad4 ASJ AF: 0.349

Gnomad4 EAS AF: 0.101

Gnomad4 SAS AF: 0.346

Gnomad4 FIN AF: 0.457

Gnomad4 NFE AF: 0.434

Gnomad4 OTH AF: 0.350

Alfa AF: 0.400 Hom.: 17179

Bravo AF: 0.303

Asia WGS AF: 0.202 AC: 705 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

BCL2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	8.2
DANN	Benign	0.77

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: rs1801018; hg19: chr18-60985879; COSMIC: COSV61374121;