rs766937547

Variant names:

• chr21-39196788-C-G
• rs766937547
• NM_033656.4:c.6281G>C

Your query was ambiguous. Multiple possible variants found:

• chr21-39196788-C-G
• chr21-39196788-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033656.4(BRWD1):​c.6281G>C​(p.Arg2094Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2094H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRWD1 NM_033656.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.820

Genes affected

BRWD1 (HGNC:12760): (bromodomain and WD repeat domain containing 1) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD) residues which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes including cell cycle progression, signal transduction, apoptosis, and gene regulation. This protein contains 2 bromodomains and multiple WD repeats. This gene is located within the Down syndrome region-2 on chromosome 21. Alternative splicing of this gene generates multiple transcript variants encoding distinct isoforms. In mouse, this gene encodes a nuclear protein that has a polyglutamine-containing region that functions as a transcriptional activation domain which may regulate chromatin remodelling and associates with a component of the SWI/SNF chromatin remodelling complex.[provided by RefSeq, Jun 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23221508).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRWD1	NM_033656.4	c.6281G>C	p.Arg2094Pro	missense_variant	Exon 41 of 41	ENST00000342449.8	NP_387505.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRWD1	ENST00000342449.8	c.6281G>C	p.Arg2094Pro	missense_variant	Exon 41 of 41	1	NM_033656.4	ENSP00000344333.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.;.
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.83	T;T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.5	M;M;M
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.019	D;D;D
Sift4G	Benign	0.26	T;T;T
Polyphen		0.97	D;D;.
Vest4		0.33
MutPred		0.54		Loss of MoRF binding (P = 0.0256);Loss of MoRF binding (P = 0.0256);Loss of MoRF binding (P = 0.0256);
MVP		0.42
MPC		0.38
ClinPred		0.81	D
GERP RS		5.5
Varity_R		0.29
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs766937547; hg19: chr21-40568714;