16-53434647-G-A

Position:

• chr16-53434647-G-A

Variant summary

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

The NM_005611.4(RBL2):​c.91G>A​(p.Ala31Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000708 in 1,411,714 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: 32)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: RBL2 NM_005611.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.89

Genes affected

RBL2 (HGNC:9894): (RB transcriptional corepressor like 2) Enables promoter-specific chromatin binding activity. Involved in regulation of lipid kinase activity. Acts upstream of or within negative regulation of gene expression. Located in chromosome; cytosol; and nuclear lumen. [provided by Alliance of Genome Resources, Apr 2022]

RBL2 (HGNC:):

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=0.0928452).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RBL2	NM_005611.4	c.91G>A	p.Ala31Thr	missense_variant	1/22	ENST00000262133.11	NP_005602.3
RBL2	NM_001323608.2	c.91G>A	p.Ala31Thr	missense_variant	1/23		NP_001310537.1
RBL2	NM_001323609.2	c.91G>A	p.Ala31Thr	missense_variant	1/21		NP_001310538.1
RBL2	NM_001323610.2	c.91G>A	p.Ala31Thr	missense_variant	1/22		NP_001310539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RBL2	ENST00000262133.11	c.91G>A	p.Ala31Thr	missense_variant	1/22	1	NM_005611.4	ENSP00000262133.6
RBL2	ENST00000567964.6	c.-154+371G>A		intron_variant		5		ENSP00000462464.1
RBL2	ENST00000680543.1	n.230G>A		non_coding_transcript_exon_variant	1/21

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000708 AC: 10 AN: 1411714 Hom.: 0 Cov.: 31 AF XY: 0.00000429 AC XY: 3 AN XY: 699834

Gnomad4 AFR exome AF: 0.0000316

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: 0.00000821

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Oct 12, 2022

The c.91G>A (p.A31T) alteration is located in exon 1 (coding exon 1) of the RBL2 gene. This alteration results from a G to A substitution at nucleotide position 91, causing the alanine (A) at amino acid position 31 to be replaced by a threonine (T). 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	-0.054	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.64	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.90	L
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.24
Sift	Benign	0.19	T
Sift4G	Benign	0.071	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.20		Gain of phosphorylation at A31 (P = 0.0034);
MVP		0.37
MPC		0.21
ClinPred		0.31	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.029
gMVP		0.24

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: rs2057936814; hg19: chr16-53468559; COSMIC: COSV105084359; COSMIC: COSV105084359;