18-22946424-C-CT

Variant names:

• chr18-22946424-C-CT
• rs541553873
• NM_002894.3:c.110-16dupT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS1

The NM_002894.3(RBBP8):​c.110-16dupT variant causes a intron change. The variant allele was found at a frequency of 0.000359 in 1,611,248 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: RBBP8 NM_002894.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.94
• 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 -6 ACMG points.

• BP6: Variant 18-22946424-C-CT is Benign according to our data. Variant chr18-22946424-C-CT is described in ClinVar as Benign. ClinVar VariationId is 1987594.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000217 (33/152094) while in subpopulation NFE AF = 0.000353 (24/68000). AF 95% confidence interval is 0.000243. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.110-16dupT		intron	N/A	NP_002885.1	Q99708-1
	RBBP8	NM_203291.2		c.110-16dupT		intron	N/A	NP_976036.1	Q99708-1
	RBBP8	NM_203292.2		c.110-16dupT		intron	N/A	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.110-16dupT		intron	N/A	ENSP00000323050.5	Q99708-1
	RBBP8	ENST00000360790.9	TSL:1	c.110-16dupT		intron	N/A	ENSP00000354024.5	I6L8A6
	RBBP8	ENST00000399722.6	TSL:1	c.110-16dupT		intron	N/A	ENSP00000382628.2	Q99708-1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000184 AC: 46 AN: 249530 AF XY: 0.000185

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000354

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000374 AC: 545 AN: 1459154 Hom.: 0 Cov.: 30 AF XY: 0.000380 AC XY: 276 AN XY: 725836

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000180 AC: 6 AN: 33402

American (AMR) AF: 0.000135 AC: 6 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25982

East Asian (EAS) AF: 0.00 AC: 0 AN: 39550

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52824

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.000474 AC: 526 AN: 1110666

Other (OTH) AF: 0.0000664 AC: 4 AN: 60270

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152094 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74292

African (AFR) AF: 0.0000965 AC: 4 AN: 41432

American (AMR) AF: 0.000197 AC: 3 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68000

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000192 Hom.: 0

Bravo AF: 0.000261

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.9
Mutation Taster		=100/0	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: rs541553873; hg19: chr18-20526387;