Genetic Variant NM_005104.4:c.-1765G>A (chr6-32968596-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005104.4(BRD2):c.-1765G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 152,992 control chromosomes in the GnomAD database, including 1,303 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.12 ( 1297 hom., cov: 33)

Exomes 𝑓: 0.12 ( 6 hom. )

Consequence

BRD2
NM_005104.4 5_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.109

Publications

19 publications found

Variant links:

COSMIC-nc: COSV66374648

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:

HLA-DMA (HGNC:4934): (major histocompatibility complex, class II, DM alpha) HLA-DMA belongs to the HLA class II alpha chain paralogues. This class II molecule is a heterodimer consisting of an alpha (DMA) and a beta chain (DMB), both anchored in the membrane. It is located in intracellular vesicles. DM plays a central role in the peptide loading of MHC class II molecules by helping to release the CLIP molecule from the peptide binding site. Class II molecules are expressed in antigen presenting cells (APC: B lymphocytes, dendritic cells, macrophages). The alpha chain is approximately 33-35 kDa and its gene contains 5 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the two extracellular domains, exon 4 encodes the transmembrane domain and the cytoplasmic tail. [provided by RefSeq, Jul 2008]

HLA-DMA links:

LOC124901302 (HGNC:):

LOC124901302 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
BRD2	NM_005104.4 link	c.-1765G>A	5_prime_UTR_variant	Exon 1 of 13	ENST00000374825.9	NP_005095.1
LOC124901302	NR_190903.1 link	n.-75C>T	upstream_gene_variant
LOC124901302	NR_190904.1 link	n.-75C>T	upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
BRD2	ENST00000374825.9 link	c.-1765G>A	5_prime_UTR_variant	Exon 1 of 13	1	NM_005104.4	ENSP00000363958.4	P25440-1
HLA-DMA	ENST00000422832.1 link	c.-12+406C>T	intron_variant	Intron 1 of 2	6		ENSP00000403122.1	F6S093
HLA-DMA	ENST00000464392.1 link	n.-152C>T	upstream_gene_variant		6

Frequencies

GnomAD3 genomes

AF:

0.118

AC:

17895

AN:

152096

Hom.:

1289

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0637

Gnomad AMI

AF:

0.190

Gnomad AMR

AF:

0.185

Gnomad ASJ

AF:

0.165

Gnomad EAS

AF:

0.254

Gnomad SAS

AF:

0.226

Gnomad FIN

AF:

0.101

Gnomad MID

AF:

0.130

Gnomad NFE

AF:

0.116

Gnomad OTH

AF:

0.128

GnomAD4 exome

AF:

0.125

AC:

AN:

778

Hom.:

Cov.:

AF XY:

0.112

AC XY:

AN XY:

598

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.0833

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.188

AC:

AN:

South Asian (SAS)

AF:

0.188

AC:

AN:

European-Finnish (FIN)

AF:

0.0667

AC:

AN:

Middle Eastern (MID)

AF:

0.125

AC:

AN:

European-Non Finnish (NFE)

AF:

0.112

AC:

AN:

580

Other (OTH)

AF:

0.278

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.118

AC:

17900

AN:

152214

Hom.:

1297

Cov.:

AF XY:

0.121

AC XY:

8988

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0636

AC:

2642

AN:

41548

American (AMR)

AF:

0.185

AC:

2834

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.165

AC:

571

AN:

3470

East Asian (EAS)

AF:

0.253

AC:

1308

AN:

5160

South Asian (SAS)

AF:

0.225

AC:

1086

AN:

4830

European-Finnish (FIN)

AF:

0.101

AC:

1073

AN:

10618

Middle Eastern (MID)

AF:

0.129

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.116

AC:

7891

AN:

67972

Other (OTH)

AF:

0.134

AC:

284

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

837

1675

2512

3350

4187

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

208

416

624

832

1040

<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:

0.115

Hom.:

2344

Bravo

AF:

0.119

Asia WGS

AF:

0.248

AC:

861

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

6.3

(source)

DANN

Benign

0.78

PhyloP100

0.11

PromoterAI

-0.10

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Computational scores

Splicing

Publications

Other links and lift over