dbSNP rs776162179: RB1:c.2212-6C>T (chr13-48464992-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_000321.3(RB1):c.2212-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 18)

Exomes 𝑓: 0.0012 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RB1
NM_000321.3 splice_region, intron

Scores

Splicing: ADA: 0.00001385

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.312

Publications

0 publications found

Variant links:

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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 13-48464992-C-T is Benign according to our data. Variant chr13-48464992-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 416483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RB1	NM_000321.3	MANE Select	c.2212-6C>T		splice_region intron	N/A	NP_000312.2	P06400
	RB1	NM_001407165.1		c.2212-6C>T		splice_region intron	N/A	NP_001394094.1	A0A3B3IS71

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
RB1	ENST00000267163.6	TSL:1 MANE Select	c.2212-6C>T	splice_region intron	N/A	ENSP00000267163.4	P06400
RB1	ENST00000467505.6	TSL:1	n.*1580-6C>T	splice_region intron	N/A	ENSP00000434702.1	Q92728
RB1	ENST00000924352.1		c.2335-6C>T	splice_region intron	N/A	ENSP00000594411.1

Frequencies

GnomAD3 genomes

AF:

0.000324

AC:

AN:

74060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000249

Gnomad AMI

AF:

0.00244

Gnomad AMR

AF:

0.000413

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00307

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000190

Gnomad OTH

AF:

0.00217

GnomAD2 exomes

AF:

0.00164

AC:

337

AN:

205610

AF XY:

0.00154

show subpopulations

Gnomad AFR exome

AF:

0.000799

Gnomad AMR exome

AF:

0.00193

Gnomad ASJ exome

AF:

0.00107

Gnomad EAS exome

AF:

0.00469

Gnomad FIN exome

AF:

0.000485

Gnomad NFE exome

AF:

0.00175

Gnomad OTH exome

AF:

0.00243

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00116

AC:

716

AN:

617786

Hom.:

Cov.:

AF XY:

0.00115

AC XY:

367

AN XY:

319804

show subpopulations

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

African (AFR)

AF:

0.00122

AC:

AN:

21350

American (AMR)

AF:

0.00283

AC:

AN:

26458

Ashkenazi Jewish (ASJ)

AF:

0.00107

AC:

AN:

13134

East Asian (EAS)

AF:

0.00359

AC:

AN:

20322

South Asian (SAS)

AF:

0.00233

AC:

100

AN:

42962

European-Finnish (FIN)

AF:

0.000414

AC:

AN:

36212

Middle Eastern (MID)

AF:

0.00103

AC:

AN:

1938

European-Non Finnish (NFE)

AF:

0.000895

AC:

384

AN:

429008

Other (OTH)

AF:

0.00102

AC:

AN:

26402

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.341

Heterozygous variant carriers

110

147

184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000324

AC:

AN:

74104

Hom.:

Cov.:

AF XY:

0.000294

AC XY:

AN XY:

34058

show subpopulations

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

African (AFR)

AF:

0.000249

AC:

AN:

28142

American (AMR)

AF:

0.000412

AC:

AN:

4850

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1762

East Asian (EAS)

AF:

0.00

AC:

AN:

2182

South Asian (SAS)

AF:

0.00

AC:

AN:

2304

European-Finnish (FIN)

AF:

0.00307

AC:

AN:

1952

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000190

AC:

AN:

31504

Other (OTH)

AF:

0.00215

AC:

AN:

932

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000717834), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.381

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Retinoblastoma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

9.5

(source)

DANN

Benign

0.42

PhyloP100

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000014

dbscSNV1_RF

Benign

0.018

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over