18-63318646-T-C

Variant names:

• chr18-63318646-T-C
• rs1801018
• NM_000633.3:c.21A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_000633.3(BCL2):​c.21A>G​(p.Thr7Thr) 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.32 (9647 hom., cov: 32)
  • Exomes 𝑓: 0.41 (125536 hom.)
• Consequence: BCL2 NM_000633.3 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.699
• Publications: 84 publications found

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

Our verdict: Benign. The variant received -14 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 VariationId is 3060318.Status of the report is no_assertion_criteria_provided, 0 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 rank	MANE	Protein	UniProt
BCL2	NM_000633.3	c.21A>G	p.Thr7Thr	synonymous_variant	Exon 2 of 3	ENST00000333681.5	NP_000624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BCL2	ENST00000333681.5	c.21A>G	p.Thr7Thr	synonymous_variant	Exon 2 of 3	1	NM_000633.3	ENSP00000329623.3

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

GnomAD2 exomes AF: 0.372 AC: 91756 AN: 246918 AF XY: 0.378

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 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

African (AFR) AF: 0.0680 AC: 2271 AN: 33418

American (AMR) AF: 0.414 AC: 18451 AN: 44572

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 9046 AN: 26076

East Asian (EAS) AF: 0.105 AC: 4153 AN: 39480

South Asian (SAS) AF: 0.368 AC: 31727 AN: 86176

European-Finnish (FIN) AF: 0.459 AC: 24325 AN: 53038

Middle Eastern (MID) AF: 0.390 AC: 2247 AN: 5764

European-Non Finnish (NFE) AF: 0.431 AC: 478709 AN: 1110988

Other (OTH) AF: 0.371 AC: 22394 AN: 60314

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

African (AFR) AF: 0.0805 AC: 3347 AN: 41568

American (AMR) AF: 0.391 AC: 5982 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 1212 AN: 3470

East Asian (EAS) AF: 0.101 AC: 525 AN: 5182

South Asian (SAS) AF: 0.346 AC: 1670 AN: 4822

European-Finnish (FIN) AF: 0.457 AC: 4837 AN: 10592

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.434 AC: 29523 AN: 67964

Other (OTH) AF: 0.350 AC: 737 AN: 2108

Alfa AF: 0.395 Hom.: 22062

Bravo AF: 0.303

Asia WGS AF: 0.202 AC: 705 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

BCL2-related disorder Benign:1

Oct 16, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		0.70
PromoterAI		-0.00050	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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