Genetic Variant NM_005104.4:c.1500_1502delGGA (chr6-32977921-TGAG-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_SupportingBS2

The NM_005104.4(BRD2):c.1500_1502delGGA(p.Glu500del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0302 in 1,612,630 control chromosomes in the GnomAD database, including 928 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.022 ( 53 hom., cov: 32)

Exomes 𝑓: 0.031 ( 875 hom. )

Consequence

BRD2
NM_005104.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2B:1

Conservation

PhyloP100: 5.63

Publications

2 publications found

Variant links:

Genes affected

BRD2 (HGNC:1103): (bromodomain containing 2) This gene encodes a transcriptional regulator that belongs to the BET (bromodomains and extra terminal domain) family of proteins. This protein associates with transcription complexes and with acetylated chromatin during mitosis, and it selectively binds to the acetylated lysine-12 residue of histone H4 via its two bromodomains. The gene maps to the major histocompatability complex (MHC) class II region on chromosome 6p21.3, but sequence comparison suggests that the protein is not involved in the immune response. This gene has been implicated in juvenile myoclonic epilepsy, a common form of epilepsy that becomes apparent in adolescence. Multiple alternatively spliced variants have been described for this gene. [provided by RefSeq, Dec 2010]

BRD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0221 (3367/152014) while in subpopulation SAS AF = 0.0522 (251/4812). AF 95% confidence interval is 0.0469. There are 53 homozygotes in GnomAd4. There are 1543 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 53 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRD2	NM_005104.4 link	c.1500_1502delGGA	p.Glu500del	disruptive_inframe_deletion	Exon 9 of 13	ENST00000374825.9	NP_005095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRD2	ENST00000374825.9 link	c.1500_1502delGGA	p.Glu500del	disruptive_inframe_deletion	Exon 9 of 13	1	NM_005104.4	ENSP00000363958.4		P25440-1

Frequencies

GnomAD3 genomes

AF:

0.0222

AC:

3372

AN:

151894

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00590

Gnomad AMI

AF:

0.156

Gnomad AMR

AF:

0.0121

Gnomad ASJ

AF:

0.0464

Gnomad EAS

AF:

0.0120

Gnomad SAS

AF:

0.0527

Gnomad FIN

AF:

0.00624

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0326

Gnomad OTH

AF:

0.0168

GnomAD2 exomes

AF:

0.0256

AC:

6312

AN:

246560

AF XY:

0.0278

show subpopulations

Gnomad AFR exome

AF:

0.00549

Gnomad AMR exome

AF:

0.0104

Gnomad ASJ exome

AF:

0.0461

Gnomad EAS exome

AF:

0.0165

Gnomad FIN exome

AF:

0.00742

Gnomad NFE exome

AF:

0.0302

Gnomad OTH exome

AF:

0.0232

GnomAD4 exome

AF:

0.0311

AC:

45361

AN:

1460616

Hom.:

875

AF XY:

0.0315

AC XY:

22917

AN XY:

726638

show subpopulations

African (AFR)

AF:

0.00612

AC:

205

AN:

33470

American (AMR)

AF:

0.0113

AC:

506

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0428

AC:

1119

AN:

26136

East Asian (EAS)

AF:

0.00778

AC:

309

AN:

39700

South Asian (SAS)

AF:

0.0479

AC:

4135

AN:

86250

European-Finnish (FIN)

AF:

0.00806

AC:

422

AN:

52328

Middle Eastern (MID)

AF:

0.0203

AC:

117

AN:

5768

European-Non Finnish (NFE)

AF:

0.0330

AC:

36729

AN:

1111870

Other (OTH)

AF:

0.0301

AC:

1819

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

2623

5246

7870

10493

13116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1396

2792

4188

5584

6980

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0221

AC:

3367

AN:

152014

Hom.:

Cov.:

AF XY:

0.0208

AC XY:

1543

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.00591

AC:

245

AN:

41458

American (AMR)

AF:

0.0121

AC:

185

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.0464

AC:

161

AN:

3468

East Asian (EAS)

AF:

0.0120

AC:

AN:

5176

South Asian (SAS)

AF:

0.0522

AC:

251

AN:

4812

European-Finnish (FIN)

AF:

0.00624

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0326

AC:

2215

AN:

67930

Other (OTH)

AF:

0.0161

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

163

325

488

650

813

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

184

230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0267

Hom.:

Bravo

AF:

0.0215

EpiCase

AF:

0.0328

EpiControl

AF:

0.0343

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 03, 2013

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

BRD2-related disorder

Benign:1

Apr 09, 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

PhyloP100

5.6

Mutation Taster

=77/23

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over