8-52636059-G-T

Position:

• chr8-52636059-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014781.5(RB1CC1):​c.4348C>A​(p.His1450Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,452,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RB1CC1 NM_014781.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.05

Genes affected

RB1CC1 (HGNC:15574): (RB1 inducible coiled-coil 1) The protein encoded by this gene interacts with signaling pathways to coordinately regulate cell growth, cell proliferation, apoptosis, autophagy, and cell migration. This tumor suppressor also enhances retinoblastoma 1 gene expression in cancer cells. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13817427).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1CC1	NM_014781.5	c.4348C>A	p.His1450Asn	missense_variant	19/24	ENST00000025008.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1CC1	ENST00000025008.10	c.4348C>A	p.His1450Asn	missense_variant	19/24	1	NM_014781.5	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452884 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 722764

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2024

The c.4348C>A (p.H1450N) alteration is located in exon 19 (coding exon 17) of the RB1CC1 gene. This alteration results from a C to A substitution at nucleotide position 4348, causing the histidine (H) at amino acid position 1450 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	22
DANN	Benign	0.90
DEOGEN2	Benign	0.33	T;.
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.057
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.82	N;N
REVEL	Benign	0.071
Sift	Uncertain	0.018	D;D
Sift4G	Benign	0.25	T;T
Polyphen		0.17	B;B
Vest4		0.46
MutPred		0.19		Loss of catalytic residue at L1452 (P = 0.0571);Loss of catalytic residue at L1452 (P = 0.0571);
MVP		0.40
MPC		0.18
ClinPred		0.68	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.35

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

LitVar

Other links and lift over

dbSNP: rs1033765128; hg19: chr8-53548619;