18-63318367-G-A

Variant names:

• chr18-63318367-G-A
• rs61733416
• NM_000633.3:c.300C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000633.3(BCL2):​c.300C>T​(p.Ala100Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,604,426 control chromosomes in the GnomAD database, including 222 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.020 (36 hom., cov: 32)
  • Exomes 𝑓: 0.015 (186 hom.)
• Consequence: BCL2 NM_000633.3 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.46
• Publications: 5 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=-0.69).
• BP6: Variant 18-63318367-G-A is Benign according to our data. Variant chr18-63318367-G-A is described in ClinVar as Benign. ClinVar VariationId is 3041306.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-1.46 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0201 (3057/152254) while in subpopulation AFR AF = 0.0355 (1477/41562). AF 95% confidence interval is 0.034. There are 36 homozygotes in GnomAd4. There are 1399 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3057 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000633.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCL2	NM_000633.3	MANE Select	c.300C>T	p.Ala100Ala	synonymous	Exon 2 of 3	NP_000624.2
	BCL2	NM_000657.3		c.300C>T	p.Ala100Ala	synonymous	Exon 2 of 2	NP_000648.2
	BCL2	NM_001438935.1		c.300C>T	p.Ala100Ala	synonymous	Exon 2 of 3	NP_001425864.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BCL2	ENST00000333681.5	TSL:1 MANE Select	c.300C>T	p.Ala100Ala	synonymous	Exon 2 of 3	ENSP00000329623.3
	BCL2	ENST00000398117.1	TSL:1	c.300C>T	p.Ala100Ala	synonymous	Exon 1 of 2	ENSP00000381185.1
	BCL2	ENST00000589955.2	TSL:6	c.300C>T	p.Ala100Ala	synonymous	Exon 1 of 1	ENSP00000466417.1

Frequencies

GnomAD3 genomes AF: 0.0201 AC: 3063 AN: 152138 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0356

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.0304

Gnomad SAS AF: 0.00973

Gnomad FIN AF: 0.00659

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0154

Gnomad OTH AF: 0.0215

GnomAD2 exomes AF: 0.0147 AC: 3475 AN: 236506 AF XY: 0.0142

Gnomad AFR exome AF: 0.0354

Gnomad AMR exome AF: 0.00993

Gnomad ASJ exome AF: 0.00396

Gnomad EAS exome AF: 0.0326

Gnomad FIN exome AF: 0.00660

Gnomad NFE exome AF: 0.0143

Gnomad OTH exome AF: 0.0139

GnomAD4 exome AF: 0.0145 AC: 21061 AN: 1452172 Hom.: 186 Cov.: 34 AF XY: 0.0143 AC XY: 10348 AN XY: 721414

African (AFR) AF: 0.0348 AC: 1163 AN: 33376

American (AMR) AF: 0.0108 AC: 478 AN: 44264

Ashkenazi Jewish (ASJ) AF: 0.00377 AC: 96 AN: 25446

East Asian (EAS) AF: 0.0232 AC: 919 AN: 39610

South Asian (SAS) AF: 0.00817 AC: 693 AN: 84780

European-Finnish (FIN) AF: 0.00727 AC: 380 AN: 52280

Middle Eastern (MID) AF: 0.00943 AC: 54 AN: 5726

European-Non Finnish (NFE) AF: 0.0147 AC: 16254 AN: 1106678

Other (OTH) AF: 0.0171 AC: 1024 AN: 60012

GnomAD4 genome AF: 0.0201 AC: 3057 AN: 152254 Hom.: 36 Cov.: 32 AF XY: 0.0188 AC XY: 1399 AN XY: 74430

African (AFR) AF: 0.0355 AC: 1477 AN: 41562

American (AMR) AF: 0.0121 AC: 185 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.0302 AC: 156 AN: 5158

South Asian (SAS) AF: 0.00933 AC: 45 AN: 4824

European-Finnish (FIN) AF: 0.00659 AC: 70 AN: 10626

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0154 AC: 1050 AN: 67996

Other (OTH) AF: 0.0213 AC: 45 AN: 2114

Alfa AF: 0.0186 Hom.: 10

Bravo AF: 0.0213

Asia WGS AF: 0.0210 AC: 73 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

BCL2-related disorder Benign:1

Feb 22, 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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	10
DANN	Benign	0.94
PhyloP100		-1.5
PromoterAI		-0.023	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: rs61733416; hg19: chr18-60985600;