18-22993471-T-C

Position:

• chr18-22993471-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002894.3(RBBP8):​c.1644T>C​(p.Asp548Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00957 in 1,614,198 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0098 (86 hom.)
• Consequence: RBBP8 NM_002894.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.39

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 18-22993471-T-C is Benign according to our data. Variant chr18-22993471-T-C is described in ClinVar as [Benign]. Clinvar id is 130104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-22993471-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.39 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00737 (1123/152330) while in subpopulation NFE AF= 0.0109 (744/68004). AF 95% confidence interval is 0.0103. There are 8 homozygotes in gnomad4. There are 514 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBBP8	NM_002894.3	c.1644T>C	p.Asp548Asp	synonymous_variant	11/19	ENST00000327155.10	NP_002885.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBBP8	ENST00000327155.10	c.1644T>C	p.Asp548Asp	synonymous_variant	11/19	1	NM_002894.3	ENSP00000323050.5

Frequencies

GnomAD3 genomes AF: 0.00738 AC: 1124 AN: 152212 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00903

Gnomad ASJ AF: 0.00923

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00612

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0109

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00785 AC: 1970 AN: 250906 Hom.: 6 AF XY: 0.00755 AC XY: 1026 AN XY: 135824

Gnomad AFR exome AF: 0.00175

Gnomad AMR exome AF: 0.00853

Gnomad ASJ exome AF: 0.00963

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00170

Gnomad FIN exome AF: 0.00647

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.00979 AC: 14318 AN: 1461868 Hom.: 86 Cov.: 32 AF XY: 0.00954 AC XY: 6935 AN XY: 727238

Gnomad4 AFR exome AF: 0.00164

Gnomad4 AMR exome AF: 0.00959

Gnomad4 ASJ exome AF: 0.00869

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00180

Gnomad4 FIN exome AF: 0.00625

Gnomad4 NFE exome AF: 0.0113

Gnomad4 OTH exome AF: 0.00871

GnomAD4 genome AF: 0.00737 AC: 1123 AN: 152330 Hom.: 8 Cov.: 33 AF XY: 0.00690 AC XY: 514 AN XY: 74498

Gnomad4 AFR AF: 0.00240

Gnomad4 AMR AF: 0.00901

Gnomad4 ASJ AF: 0.00923

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00612

Gnomad4 NFE AF: 0.0109

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00940 Hom.: 1

Bravo AF: 0.00764

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0130

EpiControl AF: 0.0133

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	RBBP8: BP4, BP7, BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 02, 2017

- -

RBBP8-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 07, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	1.0
DANN	Benign	0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

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: rs34780140; hg19: chr18-20573434;