13-48303978-ACCGCCG-ACCGCCGCCGCCG

Variant names:

• chr13-48303978-A-ACCGCCG
• rs587778823
• NM_000321.3:c.75_80dupGCCGCC

Variant summary

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

The NM_000321.3(RB1):​c.75_80dupGCCGCC​(p.Pro26_Pro27dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P27P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.54
• Publications: 4 publications found

Genes affected

RB1 (HGNC:9884): (RB transcriptional corepressor 1) The protein encoded by this gene is a negative regulator of the cell cycle and was the first tumor suppressor gene found. The encoded protein also stabilizes constitutive heterochromatin to maintain the overall chromatin structure. The active, hypophosphorylated form of the protein binds transcription factor E2F1. Defects in this gene are a cause of childhood cancer retinoblastoma (RB), bladder cancer, and osteogenic sarcoma. [provided by RefSeq, Jul 2008]

RB1 Gene-Disease associations (from GenCC):

• hereditary retinoblastoma

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Ambry Genetics
• retinoblastoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• melanoma

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000321.3. 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
	RB1	NM_000321.3	MANE Select	c.75_80dupGCCGCC	p.Pro26_Pro27dup	disruptive_inframe_insertion	Exon 1 of 27	NP_000312.2
	RB1	NM_001407165.1		c.75_80dupGCCGCC	p.Pro26_Pro27dup	disruptive_inframe_insertion	Exon 1 of 27	NP_001394094.1
	RB1	NM_001407166.1		c.75_80dupGCCGCC	p.Pro26_Pro27dup	disruptive_inframe_insertion	Exon 1 of 17	NP_001394095.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	ENST00000267163.6	TSL:1 MANE Select	c.75_80dupGCCGCC	p.Pro26_Pro27dup	disruptive_inframe_insertion	Exon 1 of 27	ENSP00000267163.4
	RB1	ENST00000467505.6	TSL:1	n.75_80dupGCCGCC		non_coding_transcript_exon	Exon 1 of 22	ENSP00000434702.1
	RB1	ENST00000650461.1		c.75_80dupGCCGCC	p.Pro26_Pro27dup	disruptive_inframe_insertion	Exon 1 of 27	ENSP00000497193.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinoblastoma Uncertain:1

Sep 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.75_80dup, results in the insertion of 2 amino acid(s) of the RB1 protein (p.Pro28_Pro29dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 827088). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Hereditary cancer-predisposing syndrome Uncertain:1

Jul 10, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.75_80dupGCCGCC variant (also known as p.P28_P29dup), located in coding exon 1 of the RB1 gene, results from an in-frame duplication of GCCGCC at nucleotide positions 75 to 80. This results in the duplication of 2 extra residues (PP) between codons 28 and 29. These amino acid positions are well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587778823; hg19: chr13-48878114;