NM_001268.4:c.1093G>A

Variant names:

• chr13-48502748-C-T
• rs148279651
• NM_001268.4:c.1093G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001268.4(RCBTB2):​c.1093G>A​(p.Val365Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000465 in 1,612,146 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00061 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (0 hom.)
• Consequence: RCBTB2 NM_001268.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.86

Genes affected

RCBTB2 (HGNC:1914): (RCC1 and BTB domain containing protein 2) This gene encodes a protein containing two C-terminal BTB/POZ domains that is related to regulator of chromosome condensation (RCC). The encoded protein may act as a guanine nucleotide exchange factor. This gene is observed to be lost or underexpressed in prostate cancers. There is a pseudogene of this gene on chromosome 10. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2013]

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057116807).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RCBTB2	NM_001268.4	c.1093G>A	p.Val365Ile	missense_variant	Exon 11 of 15	ENST00000344532.8	NP_001259.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RCBTB2	ENST00000344532.8	c.1093G>A	p.Val365Ile	missense_variant	Exon 11 of 15	1	NM_001268.4	ENSP00000345144.3

Frequencies

GnomAD3 genomes AF: 0.000611 AC: 93 AN: 152194 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00353

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000543 AC: 135 AN: 248536 Hom.: 0 AF XY: 0.000528 AC XY: 71 AN XY: 134482

Gnomad AFR exome AF: 0.0000634

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.000704

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.000361

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000651

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000449 AC: 656 AN: 1459952 Hom.: 0 Cov.: 31 AF XY: 0.000460 AC XY: 334 AN XY: 726166

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.000807

Gnomad4 ASJ exome AF: 0.000538

Gnomad4 EAS exome AF: 0.000177

Gnomad4 SAS exome AF: 0.000360

Gnomad4 FIN exome AF: 0.000206

Gnomad4 NFE exome AF: 0.000470

Gnomad4 OTH exome AF: 0.000514

GnomAD4 genome AF: 0.000611 AC: 93 AN: 152194 Hom.: 1 Cov.: 32 AF XY: 0.000847 AC XY: 63 AN XY: 74344

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00353

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000435 Hom.: 0

Bravo AF: 0.000480

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000503 AC: 61

EpiCase AF: 0.000273

EpiControl AF: 0.000772

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 23, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1093G>A (p.V365I) alteration is located in exon 11 (coding exon 8) of the RCBTB2 gene. This alteration results from a G to A substitution at nucleotide position 1093, causing the valine (V) at amino acid position 365 to be replaced by an isoleucine (I). 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	0.10
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.032	T;T;.;.
Eigen	Benign	0.095
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.057	T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.5	L;.;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.75	N;N;N;.
REVEL	Benign	0.17
Sift	Benign	0.032	D;T;D;.
Sift4G	Benign	0.23	T;T;T;T
Polyphen		0.77	P;B;P;.
Vest4		0.41
MVP		0.69
MPC		0.093
ClinPred		0.024	T
GERP RS		5.6
Varity_R		0.15
gMVP		0.59

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: rs148279651; hg19: chr13-49076884;