rs201195506

Variant names:

• chr18-23026176-G-A
• rs201195506
• NM_002894.3:c.2630G>A

Your query was ambiguous. Multiple possible variants found:

• chr18-23026176-G-A
• chr18-23026176-G-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_002894.3(RBBP8):​c.2630G>A​(p.Arg877His) variant causes a missense change. The variant allele was found at a frequency of 0.000152 in 1,613,508 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R877C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: RBBP8 NM_002894.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.15
• Publications: 0 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P
• Seckel syndrome 2

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20688409).
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000155 (227/1461410) while in subpopulation NFE AF = 0.000195 (217/1111720). AF 95% confidence interval is 0.000174. There are 0 homozygotes in GnomAdExome4. There are 111 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002894.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBBP8	NM_002894.3	MANE Select	c.2630G>A	p.Arg877His	missense	Exon 19 of 19	NP_002885.1	Q99708-1
	RBBP8	NM_203291.2		c.2630G>A	p.Arg877His	missense	Exon 19 of 19	NP_976036.1	Q99708-1
	RBBP8	NM_203292.2		c.2533G>A	p.Val845Ile	missense	Exon 18 of 18	NP_976037.1	Q99708-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBBP8	ENST00000327155.10	TSL:1 MANE Select	c.2630G>A	p.Arg877His	missense	Exon 19 of 19	ENSP00000323050.5	Q99708-1
	RBBP8	ENST00000360790.9	TSL:1	c.2645G>A	p.Arg882His	missense	Exon 19 of 19	ENSP00000354024.5	I6L8A6
	RBBP8	ENST00000399722.6	TSL:1	c.2630G>A	p.Arg877His	missense	Exon 19 of 19	ENSP00000382628.2	Q99708-1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000637 AC: 16 AN: 251120 AF XY: 0.0000810

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000155 AC: 227 AN: 1461410 Hom.: 0 Cov.: 30 AF XY: 0.000153 AC XY: 111 AN XY: 727024

African (AFR) AF: 0.000120 AC: 4 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39616

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000195 AC: 217 AN: 1111720

Other (OTH) AF: 0.0000828 AC: 5 AN: 60378

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152098 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74286

African (AFR) AF: 0.0000483 AC: 2 AN: 41426

American (AMR) AF: 0.0000655 AC: 1 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000772 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.43	T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.1	T
PhyloP100		6.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.73
MVP		0.53
MPC		0.31
ClinPred		0.39	T
GERP RS		4.9
Varity_R		0.14
gMVP		0.38
Mutation Taster		=73/27	polymorphism

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: rs201195506; hg19: chr18-20606139;