NM_002894.3:c.946C>G

Variant names:

• chr18-22992773-C-G
• rs150369515
• NM_002894.3:c.946C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002894.3(RBBP8):​c.946C>G​(p.Pro316Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,442,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. P316T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RBBP8 NM_002894.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.737
• 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: 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18481752).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBBP8	NM_002894.3	MANE Select	c.946C>G	p.Pro316Ala	missense	Exon 11 of 19	NP_002885.1
	RBBP8	NM_203291.2		c.946C>G	p.Pro316Ala	missense	Exon 11 of 19	NP_976036.1
	RBBP8	NM_203292.2		c.946C>G	p.Pro316Ala	missense	Exon 11 of 18	NP_976037.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBBP8	ENST00000327155.10	TSL:1 MANE Select	c.946C>G	p.Pro316Ala	missense	Exon 11 of 19	ENSP00000323050.5
	RBBP8	ENST00000360790.9	TSL:1	c.946C>G	p.Pro316Ala	missense	Exon 11 of 19	ENSP00000354024.5
	RBBP8	ENST00000399722.6	TSL:1	c.946C>G	p.Pro316Ala	missense	Exon 11 of 19	ENSP00000382628.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442610 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 718940

African (AFR) AF: 0.00 AC: 0 AN: 33004

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39538

South Asian (SAS) AF: 0.00 AC: 0 AN: 85748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 9.13e-7 AC: 1 AN: 1094748

Other (OTH) AF: 0.00 AC: 0 AN: 59816

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.093
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.75	T
PhyloP100		0.74
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.058
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.018	D
Polyphen		0.99	D
Vest4		0.19
MutPred		0.25		Gain of loop (P = 0.0045)
MVP		0.38
MPC		0.045
ClinPred		0.84	D
GERP RS		3.1
Varity_R		0.045
gMVP		0.096
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150369515; hg19: chr18-20572736;