chr6-32976351-C-T

Position:

• chr6-32976351-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005104.4(BRD2):​c.712C>T​(p.Leu238Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00462 in 1,613,072 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 0.0048 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (50 hom.)
• Consequence: BRD2 NM_005104.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.32

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]

BRD2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048858523).
• BP6: Variant 6-32976351-C-T is Benign according to our data. Variant chr6-32976351-C-T is described in ClinVar as [Benign]. Clinvar id is 785805.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-32976351-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRD2	NM_005104.4	c.712C>T	p.Leu238Phe	missense_variant	6/13	ENST00000374825.9	NP_005095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRD2	ENST00000374825.9	c.712C>T	p.Leu238Phe	missense_variant	6/13	1	NM_005104.4	ENSP00000363958.4

Frequencies

GnomAD3 genomes AF: 0.00480 AC: 730 AN: 152192 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.0357

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00639

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00527 AC: 1301 AN: 246892 Hom.: 13 AF XY: 0.00517 AC XY: 695 AN XY: 134488

Gnomad AFR exome AF: 0.000527

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.0392

Gnomad EAS exome AF: 0.000328

Gnomad SAS exome AF: 0.00181

Gnomad FIN exome AF: 0.00351

Gnomad NFE exome AF: 0.00615

Gnomad OTH exome AF: 0.00708

GnomAD4 exome AF: 0.00461 AC: 6730 AN: 1460762 Hom.: 50 Cov.: 43 AF XY: 0.00468 AC XY: 3401 AN XY: 726698

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.0374

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00213

Gnomad4 FIN exome AF: 0.00373

Gnomad4 NFE exome AF: 0.00442

Gnomad4 OTH exome AF: 0.00576

GnomAD4 genome AF: 0.00479 AC: 729 AN: 152310 Hom.: 4 Cov.: 32 AF XY: 0.00473 AC XY: 352 AN XY: 74490

Gnomad4 AFR AF: 0.000867

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.0357

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00639

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00759 Hom.: 21

Bravo AF: 0.00470

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000993 AC: 3

ESP6500EA AF: 0.00683 AC: 37

ExAC AF: 0.00519 AC: 614

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00627

EpiControl AF: 0.00747

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

BRD2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 02, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;T;.;.;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.65	.;.;T;.;.
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.0049	T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.7	L;L;.;L;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.97	N;N;.;N;N
REVEL	Benign	0.11
Sift	Benign	0.35	T;T;.;T;T
Sift4G	Benign	0.26	T;T;T;T;T
Polyphen		0.81	P;P;.;.;.
Vest4		0.40
MVP		0.31
ClinPred		0.027	T
GERP RS		5.3
Varity_R		0.16
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs176250; hg19: chr6-32944128; COSMIC: COSV66372779; COSMIC: COSV66372779;