13-48463741-G-C

Variant names:

• chr13-48463741-G-C
• rs121913295
• NM_000321.3:c.2117G>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000321.3(RB1):​c.2117G>C​(p.Cys706Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C706Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.92
• Publications: 0 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000321.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-48463741-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2736033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.2117G>C	p.Cys706Ser	missense_variant	Exon 21 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.2117G>C	p.Cys706Ser	missense_variant	Exon 21 of 27		NP_001394094.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RB1	ENST00000267163.6	c.2117G>C	p.Cys706Ser	missense_variant	Exon 21 of 27	1	NM_000321.3	ENSP00000267163.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.92	D;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	1.3	L;.
PhyloP100		5.9
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.6	D;.
REVEL	Uncertain	0.63
Sift	Benign	0.25	T;.
Sift4G	Benign	0.65	T;.
Polyphen		0.97	D;.
Vest4		0.56
MutPred		0.86		Gain of catalytic residue at S707 (P = 0);Gain of catalytic residue at S707 (P = 0);
MVP		0.84
MPC		1.5
ClinPred		0.99	D
GERP RS		6.1
Varity_R		0.83
gMVP		0.80
Mutation Taster		=28/72	disease causing

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

Other links and lift over

dbSNP: rs121913295; hg19: chr13-49037877;