6-32976246-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005104.4(BRD2):c.611-4C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00434 in 1,605,152 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (30 hom.)
• Consequence: BRD2 NM_005104.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001694
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.53

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-32976246-C-G is Benign according to our data. Variant chr6-32976246-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 770728.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32976246-C-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRD2	NM_005104.4	c.611-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000374825.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRD2	ENST00000374825.9	c.611-4C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_005104.4	P2

Frequencies

GnomAD3 genomes AF: 0.00249 AC: 378 AN: 151828 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00446

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00235 AC: 567 AN: 240906 Hom.: 2 AF XY: 0.00228 AC XY: 299 AN XY: 131412

Gnomad AFR exome AF: 0.00134

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.000208

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000417

Gnomad NFE exome AF: 0.00438

Gnomad OTH exome AF: 0.00272

GnomAD4 exome AF: 0.00453 AC: 6583 AN: 1453206 Hom.: 30 Cov.: 44 AF XY: 0.00439 AC XY: 3170 AN XY: 722774

Gnomad4 AFR exome AF: 0.000947

Gnomad4 AMR exome AF: 0.00129

Gnomad4 ASJ exome AF: 0.000348

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000574

Gnomad4 NFE exome AF: 0.00551

Gnomad4 OTH exome AF: 0.00577

GnomAD4 genome AF: 0.00249 AC: 378 AN: 151946 Hom.: 4 Cov.: 32 AF XY: 0.00203 AC XY: 151 AN XY: 74250

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00446

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00409 Hom.: 2

Bravo AF: 0.00275

EpiCase AF: 0.00327

EpiControl AF: 0.00445

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

BRD2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 05, 2019

This variant is classified as likely 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

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.21
Dann	Benign	0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.010
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: rs147965395; hg19: chr6-32944023; COSMIC: COSV105314239; COSMIC: COSV105314239;