rs34678569

Variant names:

• chr18-22992898-A-C
• rs34678569
• NM_002894.3:c.1071A>C

Your query was ambiguous. Multiple possible variants found:

• chr18-22992898-A-C
• chr18-22992898-A-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002894.3(RBBP8):​c.1071A>C​(p.Lys357Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,613,976 control chromosomes in the GnomAD database, including 62 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (10 hom., cov: 33)
  • Exomes 𝑓: 0.0021 (52 hom.)
• Consequence: RBBP8 NM_002894.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.728
• Publications: 8 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002441287).
• BP6: Variant 18-22992898-A-C is Benign according to our data. Variant chr18-22992898-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00586 (893/152264) while in subpopulation SAS AF = 0.0282 (136/4820). AF 95% confidence interval is 0.0244. There are 10 homozygotes in GnomAd4. There are 447 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

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.1071A>C	p.Lys357Asn	missense	Exon 11 of 19	NP_002885.1	Q99708-1
	RBBP8	NM_203291.2		c.1071A>C	p.Lys357Asn	missense	Exon 11 of 19	NP_976036.1	Q99708-1
	RBBP8	NM_203292.2		c.1071A>C	p.Lys357Asn	missense	Exon 11 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.1071A>C	p.Lys357Asn	missense	Exon 11 of 19	ENSP00000323050.5	Q99708-1
	RBBP8	ENST00000360790.9	TSL:1	c.1071A>C	p.Lys357Asn	missense	Exon 11 of 19	ENSP00000354024.5	I6L8A6
	RBBP8	ENST00000399722.6	TSL:1	c.1071A>C	p.Lys357Asn	missense	Exon 11 of 19	ENSP00000382628.2	Q99708-1

Frequencies

GnomAD3 genomes AF: 0.00584 AC: 888 AN: 152146 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.0175

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0276

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00431 AC: 1082 AN: 251142 AF XY: 0.00472

Gnomad AFR exome AF: 0.0187

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00208 AC: 3047 AN: 1461712 Hom.: 52 Cov.: 32 AF XY: 0.00265 AC XY: 1927 AN XY: 727158

African (AFR) AF: 0.0189 AC: 634 AN: 33472

American (AMR) AF: 0.000626 AC: 28 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.000303 AC: 12 AN: 39664

South Asian (SAS) AF: 0.0251 AC: 2163 AN: 86236

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

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5764

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111938

Other (OTH) AF: 0.00296 AC: 179 AN: 60386

GnomAD4 genome AF: 0.00586 AC: 893 AN: 152264 Hom.: 10 Cov.: 33 AF XY: 0.00600 AC XY: 447 AN XY: 74456

African (AFR) AF: 0.0174 AC: 725 AN: 41550

American (AMR) AF: 0.00131 AC: 20 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5188

South Asian (SAS) AF: 0.0282 AC: 136 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68020

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00145 Hom.: 7

Bravo AF: 0.00573

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0161 AC: 71

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00501 AC: 608

Asia WGS AF: 0.0150 AC: 52 AN: 3476

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)
-	-	1	RBBP8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.059
DANN	Benign	0.40
DEOGEN2	Benign	0.070	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.73
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.54	N
REVEL	Benign	0.017
Sift	Benign	0.70	T
Sift4G	Benign	0.64	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.087		Gain of loop (P = 0.002)
MVP		0.040
MPC		0.050
ClinPred		0.00027	T
GERP RS		-1.8
Varity_R		0.040
gMVP		0.055
Mutation Taster		=100/0	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: rs34678569; hg19: chr18-20572861; COSMIC: COSV107377663; COSMIC: COSV107377663;