rs140295451

Positions:

chr18-22991000-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002894.3(RBBP8):c.871A>G(p.Lys291Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000861 in 1,613,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

RBBP8
NM_002894.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.48

Variant links:

Genes affected

RBBP8 (HGNC:9891): (RB binding protein 8, endonuclease) The protein encoded by this gene is a ubiquitously expressed nuclear protein. It is found among several proteins that bind directly to retinoblastoma protein, which regulates cell proliferation. This protein complexes with transcriptional co-repressor CTBP. It is also associated with BRCA1 and is thought to modulate the functions of BRCA1 in transcriptional regulation, DNA repair, and/or cell cycle checkpoint control. It is suggested that this gene may itself be a tumor suppressor acting in the same pathway as BRCA1. Three transcript variants encoding two different isoforms have been found for this gene. More transcript variants exist, but their full-length natures have not been determined. [provided by RefSeq, Jul 2008]

RBBP8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.01595977).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBBP8	NM_002894.3 linkuse as main transcript	c.871A>G	p.Lys291Glu	missense_variant	10/19	ENST00000327155.10	NP_002885.1	Q99708-1A0A024RC34

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBBP8	ENST00000327155.10 linkuse as main transcript	c.871A>G	p.Lys291Glu	missense_variant	10/19	1	NM_002894.3	ENSP00000323050.5		Q99708-1

Frequencies

GnomAD3 genomes

AF:

0.000466

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000123

AC:

AN:

251250

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.00191

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000465

AC:

AN:

1461524

Hom.:

Cov.:

AF XY:

0.0000399

AC XY:

AN XY:

727060

show subpopulations

Gnomad4 AFR exome

AF:

0.00185

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.000466

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00161

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.0000808

Hom.:

Bravo

AF:

0.000533

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000157

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 24, 2021	This sequence change replaces lysine with glutamic acid at codon 291 of the RBBP8 protein (p.Lys291Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs140295451, ExAC 0.2%). This variant has not been reported in the literature in individuals affected with RBBP8-related conditions. ClinVar contains an entry for this variant (Variation ID: 212024). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Sep 02, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;T;.;T;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.82

.;T;T;T;T

M_CAP

Benign

0.0051

MetaRNN

Benign

0.016

T;T;T;T;T

MetaSVM

Benign

-0.92

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.80

N;N;N;N;N

REVEL

Benign

0.057

Sift

Uncertain

0.0090

D;D;D;D;D

Sift4G

Benign

0.084

T;T;T;T;T

Polyphen

0.77

P;P;.;.;.

Vest4

0.52

MVP

0.47

MPC

0.31

ClinPred

0.18

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over