rs3918143

Variant names:

• chr6-32977848-C-T
• rs3918143
• NM_005104.4:c.1421C>T
• BRD2 p.Ala474Val

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005104.4(BRD2):​c.1421C>T​(p.Ala474Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0308 in 1,613,002 control chromosomes in the GnomAD database, including 859 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.024 (63 hom., cov: 32)
  • Exomes 𝑓: 0.031 (796 hom.)
• Consequence: BRD2 NM_005104.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.50
• Publications: 23 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033878982).
• BP6: Variant 6-32977848-C-T is Benign according to our data. Variant chr6-32977848-C-T is described in ClinVar as Benign. ClinVar VariationId is 3055955.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0236 (3597/152196) while in subpopulation SAS AF = 0.0388 (187/4818). AF 95% confidence interval is 0.0343. There are 63 homozygotes in GnomAd4. There are 1720 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 63 gene

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.1421C>T	p.Ala474Val	missense	Exon 9 of 13	NP_005095.1	P25440-1
	BRD2	NM_001199455.1		c.1421C>T	p.Ala474Val	missense	Exon 8 of 13	NP_001186384.1	P25440-2
	BRD2	NM_001113182.3		c.1421C>T	p.Ala474Val	missense	Exon 9 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.1421C>T	p.Ala474Val	missense	Exon 9 of 13	ENSP00000363958.4	P25440-1
	BRD2	ENST00000395287.5	TSL:1	c.1421C>T	p.Ala474Val	missense	Exon 8 of 13	ENSP00000378702.1	P25440-2
	BRD2	ENST00000449025.5	TSL:1	c.1436C>T	p.Ala479Val	missense	Exon 8 of 12	ENSP00000409613.1	H0Y6K2

Frequencies

GnomAD3 genomes AF: 0.0237 AC: 3597 AN: 152078 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.00647

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0244

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.0247

Gnomad SAS AF: 0.0384

Gnomad FIN AF: 0.0141

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0351

Gnomad OTH AF: 0.0272

GnomAD2 exomes AF: 0.0293 AC: 7213 AN: 246574 AF XY: 0.0305

Gnomad AFR exome AF: 0.00662

Gnomad AMR exome AF: 0.0251

Gnomad ASJ exome AF: 0.0130

Gnomad EAS exome AF: 0.0240

Gnomad FIN exome AF: 0.0135

Gnomad NFE exome AF: 0.0348

Gnomad OTH exome AF: 0.0344

GnomAD4 exome AF: 0.0315 AC: 46009 AN: 1460806 Hom.: 796 Cov.: 63 AF XY: 0.0321 AC XY: 23328 AN XY: 726720

African (AFR) AF: 0.00484 AC: 162 AN: 33480

American (AMR) AF: 0.0255 AC: 1139 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0131 AC: 343 AN: 26136

East Asian (EAS) AF: 0.0161 AC: 641 AN: 39700

South Asian (SAS) AF: 0.0447 AC: 3853 AN: 86258

European-Finnish (FIN) AF: 0.0151 AC: 791 AN: 52348

Middle Eastern (MID) AF: 0.0106 AC: 61 AN: 5768

European-Non Finnish (NFE) AF: 0.0335 AC: 37305 AN: 1112006

Other (OTH) AF: 0.0284 AC: 1714 AN: 60386

GnomAD4 genome AF: 0.0236 AC: 3597 AN: 152196 Hom.: 63 Cov.: 32 AF XY: 0.0231 AC XY: 1720 AN XY: 74406

African (AFR) AF: 0.00645 AC: 268 AN: 41528

American (AMR) AF: 0.0243 AC: 372 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3466

East Asian (EAS) AF: 0.0245 AC: 127 AN: 5174

South Asian (SAS) AF: 0.0388 AC: 187 AN: 4818

European-Finnish (FIN) AF: 0.0141 AC: 149 AN: 10602

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0351 AC: 2385 AN: 67992

Other (OTH) AF: 0.0269 AC: 57 AN: 2116

Alfa AF: 0.0311 Hom.: 342

Bravo AF: 0.0233

Asia WGS AF: 0.0480 AC: 169 AN: 3478

EpiCase AF: 0.0328

EpiControl AF: 0.0344

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	BRD2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Benign	0.87
DEOGEN2	Benign	0.070	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.5
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.080
Sift	Benign	0.26	T
Sift4G	Benign	0.41	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.057
gMVP		0.17
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3918143;

hg19: chr6-32945625;