rs7243256

Variant names:

• chr18-22936411-C-A
• rs7243256
• NM_002894.3:c.-98-343C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002894.3(RBBP8):​c.-98-343C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.679 in 151,644 control chromosomes in the GnomAD database, including 35,810 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.68 (35810 hom., cov: 32)
• Consequence: RBBP8 NM_002894.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.21
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• Jawad syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet
• Seckel syndrome 2

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• Seckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 18-22936411-C-A is Benign according to our data. Variant chr18-22936411-C-A is described in ClinVar as Benign. ClinVar VariationId is 684037.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.757 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBBP8	NM_002894.3	c.-98-343C>A		intron_variant	Intron 1 of 18	ENST00000327155.10	NP_002885.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBBP8	ENST00000327155.10	c.-98-343C>A		intron_variant	Intron 1 of 18	1	NM_002894.3	ENSP00000323050.5

Frequencies

GnomAD3 genomes AF: 0.680 AC: 102967 AN: 151524 Hom.: 35796 Cov.: 32

Gnomad AFR AF: 0.551

Gnomad AMI AF: 0.572

Gnomad AMR AF: 0.660

Gnomad ASJ AF: 0.837

Gnomad EAS AF: 0.456

Gnomad SAS AF: 0.704

Gnomad FIN AF: 0.717

Gnomad MID AF: 0.835

Gnomad NFE AF: 0.762

Gnomad OTH AF: 0.723

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.679 AC: 103014 AN: 151644 Hom.: 35810 Cov.: 32 AF XY: 0.679 AC XY: 50327 AN XY: 74108

African (AFR) AF: 0.552 AC: 22785 AN: 41314

American (AMR) AF: 0.659 AC: 10061 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.837 AC: 2896 AN: 3462

East Asian (EAS) AF: 0.455 AC: 2338 AN: 5136

South Asian (SAS) AF: 0.704 AC: 3390 AN: 4812

European-Finnish (FIN) AF: 0.717 AC: 7512 AN: 10482

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.762 AC: 51752 AN: 67872

Other (OTH) AF: 0.718 AC: 1516 AN: 2110

Alfa AF: 0.742 Hom.: 21079

Bravo AF: 0.664

Asia WGS AF: 0.579 AC: 2012 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.21
DANN	Benign	0.38
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7243256; hg19: chr18-20516374;