13-48465008-G-C

Position:

• chr13-48465008-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000321.3(RB1):​c.2222G>C​(p.Arg741Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.66

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RB1	NM_000321.3	c.2222G>C	p.Arg741Pro	missense_variant	22/27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.2222G>C	p.Arg741Pro	missense_variant	22/27		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.2222G>C	p.Arg741Pro	missense_variant	22/27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.2222G>C	p.Arg741Pro	missense_variant	22/27			ENSP00000497193.1
RB1	ENST00000643064.1	c.192+83565G>C		intron_variant				ENSP00000496005.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 23, 2024

The p.R741P variant (also known as c.2222G>C), located in coding exon 22 of the RB1 gene, results from a G to C substitution at nucleotide position 2222. The arginine at codon 741 is replaced by proline, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.076	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Benign	1.4	L;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.6	D;.
REVEL	Pathogenic	0.77
Sift	Benign	0.073	T;.
Sift4G	Benign	0.16	T;.
Polyphen		0.99	D;.
Vest4		0.76
MutPred		0.55		Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);
MVP		0.95
MPC		1.5
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.94
gMVP		0.84

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-49039144;