13-48459693-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1BP4BP6BS2

The NM_000321.3(RB1):c.1966C>T(p.Arg656Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,613,844 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R656Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00055 ( 1 hom., cov: 30)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

RB1
NM_000321.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:13

Conservation

PhyloP100: 2.98

Publications

18 publications found

Variant links:

COSMIC-nc: COSV57301791

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

RB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 25 uncertain in NM_000321.3

BP4

Computational evidence support a benign effect (MetaRNN=0.28030014).

BP6

Variant 13-48459693-C-T is Benign according to our data. Variant chr13-48459693-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41683.

BS2

High AC in GnomAd4 at 83 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3 link	c.1966C>T	p.Arg656Trp	missense_variant	Exon 20 of 27	ENST00000267163.6	NP_000312.2	P06400A0A024RDV3
RB1	NM_001407165.1 link	c.1966C>T	p.Arg656Trp	missense_variant	Exon 20 of 27		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6 link	c.1966C>T	p.Arg656Trp	missense_variant	Exon 20 of 27	1	NM_000321.3	ENSP00000267163.4		P06400

Frequencies

GnomAD3 genomes

AF:

0.000546

AC:

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000850

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000882

Gnomad OTH

AF:

0.000481

GnomAD2 exomes

AF:

0.000664

AC:

167

AN:

251334

AF XY:

0.000662

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00102

Gnomad NFE exome

AF:

0.00100

Gnomad OTH exome

AF:

0.000979

GnomAD4 exome

AF:

0.00106

AC:

1546

AN:

1461794

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

743

AN XY:

727206

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33478

American (AMR)

AF:

0.000402

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.000128

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00107

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00127

AC:

1413

AN:

1111944

Other (OTH)

AF:

0.000662

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

161

241

322

402

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000546

AC:

AN:

152050

Hom.:

Cov.:

AF XY:

0.000646

AC XY:

AN XY:

74280

show subpopulations

African (AFR)

AF:

0.000242

AC:

AN:

41384

American (AMR)

AF:

0.000196

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000850

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000882

AC:

AN:

68008

Other (OTH)

AF:

0.000481

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000827

Hom.:

Bravo

AF:

0.000506

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000577

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

May 21, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29961174, 26919633, 25452114, 25148578, 15884040, 24688104, 16269091, 12541220, 24082139, 24448499, 22703879) -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RB1: BS1 -

May 06, 2014

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Retinoblastoma

Benign:5

May 20, 2024

Genetic Diagnostic Laboratory, University of Pennsylvania School of Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Case and Pedigree Information: BILATERAL CASES:1, UNILATERAL CASES:0, TOTAL CASES:1, PEDIGREES:1. ACMG Codes Applied:BS1, BP4 -

May 02, 2022

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 06, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1Benign:2

Jul 11, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: RB1 c.1966C>T (p.Arg656Trp) results in a non-conservative amino acid change located in the Retinoblastoma-associated protein, B-box domain (IPR002719) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00066 in 251334 control chromosomes. The observed variant frequency is approximately 16 fold of the estimated maximal expected allele frequency for a pathogenic variant in RB1 causing Retinoblastoma phenotype (4.2e-05), strongly suggesting that the variant is benign. Although appearing in the literature, to our knowledge, no penetrant association of c.1966C>T in individuals affected with Retinoblastoma and no experimental evidence demonstrating its impact on protein function have been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a predominant consensus as benign/likely benign (n=5) (VUS, n=2). Based on the evidence outlined above, the variant was classified as likely benign. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

Oct 20, 2020

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

May 14, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Ovarian cancer

Benign:1

Jan 01, 2022

Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

RB1-related disorder

Benign:1

Aug 05, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

0.0025

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.075

MetaRNN

Benign

0.28

T;T

MetaSVM

Uncertain

0.20

MutationAssessor

Benign

1.6

L;.

PhyloP100

3.0

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.5

D;.

REVEL

Pathogenic

0.69

Sift

Benign

0.045

D;.

Sift4G

Benign

0.077

T;.

Polyphen

0.93

P;.

Vest4

0.43

MVP

0.94

MPC

0.51

ClinPred

0.080

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.72

gMVP

0.65

Mutation Taster

=63/37

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over