chr8-52645747-A-T

Position:

• chr8-52645747-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_014781.5(RB1CC1):​c.3942T>A​(p.Asn1314Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0088 in 1,612,838 control chromosomes in the GnomAD database, including 76 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0062 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0091 (72 hom.)
• Consequence: RB1CC1 NM_014781.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.357

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007832736).
• BP6: Variant 8-52645747-A-T is Benign according to our data. Variant chr8-52645747-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 789296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 950 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RB1CC1	NM_014781.5	c.3942T>A	p.Asn1314Lys	missense_variant	16/24	ENST00000025008.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RB1CC1	ENST00000025008.10	c.3942T>A	p.Asn1314Lys	missense_variant	16/24	1	NM_014781.5	P4
RB1CC1	ENST00000435644.6	c.3942T>A	p.Asn1314Lys	missense_variant	16/24	1		A1
RB1CC1	ENST00000521611.1	n.386-22276T>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00624 AC: 950 AN: 152170 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00169

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.00396

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0103

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00672 AC: 1677 AN: 249598 Hom.: 13 AF XY: 0.00727 AC XY: 981 AN XY: 134878

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00309

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00296

Gnomad SAS exome AF: 0.00842

Gnomad FIN exome AF: 0.00421

Gnomad NFE exome AF: 0.00959

Gnomad OTH exome AF: 0.00805

GnomAD4 exome AF: 0.00907 AC: 13250 AN: 1460550 Hom.: 72 Cov.: 31 AF XY: 0.00897 AC XY: 6514 AN XY: 726540

Gnomad4 AFR exome AF: 0.00138

Gnomad4 AMR exome AF: 0.00368

Gnomad4 ASJ exome AF: 0.00264

Gnomad4 EAS exome AF: 0.00415

Gnomad4 SAS exome AF: 0.00858

Gnomad4 FIN exome AF: 0.00465

Gnomad4 NFE exome AF: 0.0102

Gnomad4 OTH exome AF: 0.00802

GnomAD4 genome AF: 0.00624 AC: 950 AN: 152288 Hom.: 4 Cov.: 32 AF XY: 0.00568 AC XY: 423 AN XY: 74466

Gnomad4 AFR AF: 0.00171

Gnomad4 AMR AF: 0.00530

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.00704

Gnomad4 FIN AF: 0.00396

Gnomad4 NFE AF: 0.0103

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00805 Hom.: 6

Bravo AF: 0.00598

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.0101 AC: 87

ExAC AF: 0.00689 AC: 836

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.00933

EpiControl AF: 0.00902

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2022	RB1CC1: BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.97	D;D
MetaRNN	Benign	0.0078	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.15
Sift	Benign	0.067	T;T
Sift4G	Benign	0.12	T;T
Polyphen		1.0	D;D
Vest4		0.64
MutPred		0.097		Gain of ubiquitination at N1314 (P = 0.009);Gain of ubiquitination at N1314 (P = 0.009);
MVP		0.51
MPC		0.72
ClinPred		0.014	T
GERP RS		4.3
Varity_R		0.14
gMVP		0.42

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: rs34701924; hg19: chr8-53558307; COSMIC: COSV99075587; COSMIC: COSV99075587;