6-32974578-C-G

Position:

• chr6-32974578-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_005104.4(BRD2):​c.146C>G​(p.Ala49Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0155 in 1,614,232 control chromosomes in the GnomAD database, including 270 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A49S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (18 hom., cov: 32)
  • Exomes 𝑓: 0.016 (252 hom.)
• Consequence: BRD2 NM_005104.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.61

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0046857).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0124 (1895/152348) while in subpopulation SAS AF= 0.029 (140/4824). AF 95% confidence interval is 0.0251. There are 18 homozygotes in gnomad4. There are 951 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRD2	NM_005104.4	c.146C>G	p.Ala49Gly	missense_variant	3/13	ENST00000374825.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRD2	ENST00000374825.9	c.146C>G	p.Ala49Gly	missense_variant	3/13	1	NM_005104.4	P2

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1897 AN: 152230 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0292

Gnomad FIN AF: 0.0153

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0177

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.0170 AC: 4282 AN: 251466 Hom.: 59 AF XY: 0.0188 AC XY: 2556 AN XY: 135912

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00969

Gnomad ASJ exome AF: 0.0103

Gnomad EAS exome AF: 0.00114

Gnomad SAS exome AF: 0.0362

Gnomad FIN exome AF: 0.0193

Gnomad NFE exome AF: 0.0187

Gnomad OTH exome AF: 0.0218

GnomAD4 exome AF: 0.0159 AC: 23188 AN: 1461884 Hom.: 252 Cov.: 34 AF XY: 0.0165 AC XY: 12022 AN XY: 727242

Gnomad4 AFR exome AF: 0.00230

Gnomad4 AMR exome AF: 0.0103

Gnomad4 ASJ exome AF: 0.00968

Gnomad4 EAS exome AF: 0.000907

Gnomad4 SAS exome AF: 0.0359

Gnomad4 FIN exome AF: 0.0192

Gnomad4 NFE exome AF: 0.0154

Gnomad4 OTH exome AF: 0.0153

GnomAD4 genome AF: 0.0124 AC: 1895 AN: 152348 Hom.: 18 Cov.: 32 AF XY: 0.0128 AC XY: 951 AN XY: 74506

Gnomad4 AFR AF: 0.00286

Gnomad4 AMR AF: 0.0114

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00231

Gnomad4 SAS AF: 0.0290

Gnomad4 FIN AF: 0.0153

Gnomad4 NFE AF: 0.0177

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.0163 Hom.: 9

Bravo AF: 0.0117

ExAC AF: 0.0180 AC: 2189

Asia WGS AF: 0.0120 AC: 40 AN: 3478

EpiCase AF: 0.0204

EpiControl AF: 0.0194

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.46
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T;.;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	.;.;D;.;.
MetaRNN	Benign	0.0047	T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.6	L;L;.;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.1	N;N;.;N;N
REVEL	Benign	0.13
Sift	Benign	0.039	D;D;.;D;D
Sift4G	Benign	0.21	T;T;T;T;D
Polyphen		0.78	P;P;.;.;.
Vest4		0.50
ClinPred		0.019	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.15
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3918144; hg19: chr6-32942355; COSMIC: COSV66374134; COSMIC: COSV66374134;