chr6-32974717-C-A

Variant names:

• chr6-32974717-C-A
• rs375791386
• NM_005104.4:c.285C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005104.4(BRD2):​c.285C>A​(p.Phe95Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,842 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F95F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BRD2 NM_005104.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0180
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005104.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRD2	NM_005104.4	MANE Select	c.285C>A	p.Phe95Leu	missense	Exon 3 of 13	NP_005095.1	P25440-1
	BRD2	NM_001199455.1		c.285C>A	p.Phe95Leu	missense	Exon 2 of 13	NP_001186384.1	P25440-2
	BRD2	NM_001113182.3		c.285C>A	p.Phe95Leu	missense	Exon 3 of 13	NP_001106653.1	P25440-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRD2	ENST00000374825.9	TSL:1 MANE Select	c.285C>A	p.Phe95Leu	missense	Exon 3 of 13	ENSP00000363958.4	P25440-1
	BRD2	ENST00000395287.5	TSL:1	c.285C>A	p.Phe95Leu	missense	Exon 2 of 13	ENSP00000378702.1	P25440-2
	BRD2	ENST00000449025.5	TSL:1	c.300C>A	p.Phe100Leu	missense	Exon 2 of 12	ENSP00000409613.1	H0Y6K2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461842 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 727218

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.018
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.047	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.46		Gain of catalytic residue at F95 (P = 0.0155)
MVP		0.69
ClinPred		0.99	D
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.46
gMVP		0.66
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs375791386; hg19: chr6-32942494;