rs3918143

Positions:

• chr6-32977848-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.024 (63 hom., cov: 32)
  • Exomes 𝑓: 0.031 (796 hom.)
• Consequence: BRD2 NM_005104.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.50

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 -14 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 id is 3055955.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-32977848-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 63 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRD2	NM_005104.4	c.1421C>T	p.Ala474Val	missense_variant	9/13	ENST00000374825.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRD2	ENST00000374825.9	c.1421C>T	p.Ala474Val	missense_variant	9/13	1	NM_005104.4	P2

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

GnomAD3 exomes AF: 0.0293 AC: 7213 AN: 246574 Hom.: 126 AF XY: 0.0305 AC XY: 4100 AN XY: 134380

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 SAS exome AF: 0.0439

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

Gnomad4 AFR exome AF: 0.00484

Gnomad4 AMR exome AF: 0.0255

Gnomad4 ASJ exome AF: 0.0131

Gnomad4 EAS exome AF: 0.0161

Gnomad4 SAS exome AF: 0.0447

Gnomad4 FIN exome AF: 0.0151

Gnomad4 NFE exome AF: 0.0335

Gnomad4 OTH exome AF: 0.0284

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

Gnomad4 AFR AF: 0.00645

Gnomad4 AMR AF: 0.0243

Gnomad4 ASJ AF: 0.0115

Gnomad4 EAS AF: 0.0245

Gnomad4 SAS AF: 0.0388

Gnomad4 FIN AF: 0.0141

Gnomad4 NFE AF: 0.0351

Gnomad4 OTH AF: 0.0269

Alfa AF: 0.0316 Hom.: 160

Bravo AF: 0.0233

TwinsUK AF: 0.0345 AC: 128

ALSPAC AF: 0.0306 AC: 118

ESP6500AA AF: 0.00860 AC: 26

ESP6500EA AF: 0.0344 AC: 186

ExAC AF: 0.0295 AC: 3493

Asia WGS AF: 0.0480 AC: 169 AN: 3478

EpiCase AF: 0.0328

EpiControl AF: 0.0344

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

BRD2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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;T;.;.;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.57	D
MetaRNN	Benign	0.0034	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N;N;.;N;.
MutationTaster	Benign	0.97	N;N;N;N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.28	N;N;.;N;N
REVEL	Benign	0.080
Sift	Benign	0.26	T;T;.;T;T
Sift4G	Benign	0.41	T;T;T;T;T
Polyphen		0.0020	B;B;.;.;.
Vest4		0.063
ClinPred		0.0021	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.057
gMVP		0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs3918143; hg19: chr6-32945625;