13-48463769-G-C

Variant names:

• chr13-48463769-G-C
• NM_000321.3:c.2145G>C

Variant summary

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

The NM_000321.3(RB1):​c.2145G>C​(p.Lys715Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RB1 NM_000321.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.32

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 rank	MANE	Protein	UniProt
RB1	NM_000321.3	c.2145G>C	p.Lys715Asn	missense_variant	Exon 21 of 27	ENST00000267163.6	NP_000312.2
RB1	NM_001407165.1	c.2145G>C	p.Lys715Asn	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.2145G>C	p.Lys715Asn	missense_variant	Exon 21 of 27	1	NM_000321.3	ENSP00000267163.4
RB1	ENST00000650461.1	c.2145G>C	p.Lys715Asn	missense_variant	Exon 21 of 27			ENSP00000497193.1
RB1	ENST00000643064.1	c.192+82326G>C		intron_variant	Intron 1 of 1			ENSP00000496005.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.071	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	1.6	L;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-1.9	N;.
REVEL	Uncertain	0.62
Sift	Uncertain	0.015	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.69
MutPred		0.56		Gain of catalytic residue at K713 (P = 0);Gain of catalytic residue at K713 (P = 0);
MVP		0.88
MPC		1.4
ClinPred		0.92	D
GERP RS		5.2
Varity_R		0.84
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr13-49037905; COSMIC: COSV57303907;