13-48464992-C-T

Variant names:

• chr13-48464992-C-T
• rs776162179
• NM_000321.3:c.2212-6C>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_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

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 Benign. Variant got -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 [Likely_benign]. Clinvar id is 416483.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.2212-6C>T		splice_region_variant, intron_variant	Intron 21 of 26	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.2212-6C>T		splice_region_variant, intron_variant	Intron 21 of 26		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.2212-6C>T		splice_region_variant, intron_variant	Intron 21 of 26	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.2212-6C>T		splice_region_variant, intron_variant	Intron 21 of 26			ENSP00000497193.1
RB1	ENST00000643064.1	c.192+83549C>T		intron_variant	Intron 1 of 1			ENSP00000496005.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 24 AN: 74060 Hom.: 0 Cov.: 18 FAILED QC

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

GnomAD3 exomes AF: 0.00164 AC: 337 AN: 205610 Hom.: 0 AF XY: 0.00154 AC XY: 173 AN XY: 112368

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 SAS exome AF: 0.000791

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.: 0 Cov.: 25 AF XY: 0.00115 AC XY: 367 AN XY: 319804

Gnomad4 AFR exome AF: 0.00122

Gnomad4 AMR exome AF: 0.00283

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.00359

Gnomad4 SAS exome AF: 0.00233

Gnomad4 FIN exome AF: 0.000414

Gnomad4 NFE exome AF: 0.000895

Gnomad4 OTH exome AF: 0.00102

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000324 AC: 24 AN: 74104 Hom.: 0 Cov.: 18 AF XY: 0.000294 AC XY: 10 AN XY: 34058

Gnomad4 AFR AF: 0.000249

Gnomad4 AMR AF: 0.000412

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00307

Gnomad4 NFE AF: 0.000190

Gnomad4 OTH AF: 0.00215

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

May 07, 2020

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RB1 c.2212-6C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0016 in 205610 control chromosomes, predominantly at a frequency of 0.0047 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 113 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 a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.2212-6C>T in individuals affected with Retinoblastoma and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Retinoblastoma Benign:1

Jul 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	9.5
DANN	Benign	0.42

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

LitVar

Other links and lift over

dbSNP: rs776162179; hg19: chr13-49039128; COSMIC: COSV57327503;