6-32978187-G-T

Position:

• chr6-32978187-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005104.4(BRD2):​c.1640G>T​(p.Arg547Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,754 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R547K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRD2 NM_005104.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.75

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31060934).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRD2	NM_005104.4	c.1640G>T	p.Arg547Met	missense_variant	10/13	ENST00000374825.9	NP_005095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRD2	ENST00000374825.9	c.1640G>T	p.Arg547Met	missense_variant	10/13	1	NM_005104.4	ENSP00000363958	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460754 Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0 AN XY: 726694

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Benign	0.34	T;T;.;.;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	.;.;T;.;.
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.31	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L;L;.;L;.
MutationTaster	Benign	0.74	D;D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.9	D;D;.;D;D
REVEL	Benign	0.11
Sift	Uncertain	0.0010	D;D;.;D;D
Sift4G	Uncertain	0.010	D;D;D;D;D
Polyphen		0.88	P;P;.;.;.
Vest4		0.41
MutPred		0.18		Loss of methylation at K548 (P = 0.0188);Loss of methylation at K548 (P = 0.0188);Loss of methylation at K548 (P = 0.0188);Loss of methylation at K548 (P = 0.0188);.;
MVP		0.61
ClinPred		0.95	D
GERP RS		4.5
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		3.3
Varity_R		0.10
gMVP		0.30

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

LitVar

Other links and lift over

dbSNP: rs1049369; hg19: chr6-32945964;