chr16-53470809-T-C

Variant names:

• chr16-53470809-T-C
• rs10748
• NM_005611.4:c.2590T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_005611.4(RBL2):​c.2590T>C​(p.Leu864Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.469 in 1,613,868 control chromosomes in the GnomAD database, including 186,193 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.54 (24222 hom., cov: 32)
  • Exomes 𝑓: 0.46 (161971 hom.)
• Consequence: RBL2 NM_005611.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.64
• Publications: 35 publications found

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 Gene-Disease associations (from GenCC):

• Brunet-Wagner neurodevelopmental syndrome

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP7: Synonymous conserved (PhyloP=1.64 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.776 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RBL2	NM_005611.4	c.2590T>C	p.Leu864Leu	synonymous_variant	Exon 17 of 22	ENST00000262133.11	NP_005602.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RBL2	ENST00000262133.11	c.2590T>C	p.Leu864Leu	synonymous_variant	Exon 17 of 22	1	NM_005611.4	ENSP00000262133.6
RBL2	ENST00000379935.8	n.2289T>C		non_coding_transcript_exon_variant	Exon 16 of 21	1
RBL2	ENST00000680543.1	n.4381T>C		non_coding_transcript_exon_variant	Exon 15 of 21

Frequencies

GnomAD3 genomes AF: 0.538 AC: 81716 AN: 151962 Hom.: 24178 Cov.: 32

Gnomad AFR AF: 0.783

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.446

Gnomad ASJ AF: 0.592

Gnomad EAS AF: 0.182

Gnomad SAS AF: 0.472

Gnomad FIN AF: 0.349

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.469

Gnomad OTH AF: 0.545

GnomAD2 exomes AF: 0.440 AC: 110554 AN: 251234 AF XY: 0.445

Gnomad AFR exome AF: 0.782

Gnomad AMR exome AF: 0.286

Gnomad ASJ exome AF: 0.590

Gnomad EAS exome AF: 0.195

Gnomad FIN exome AF: 0.347

Gnomad NFE exome AF: 0.468

Gnomad OTH exome AF: 0.474

GnomAD4 exome AF: 0.462 AC: 675213 AN: 1461788 Hom.: 161971 Cov.: 55 AF XY: 0.464 AC XY: 337264 AN XY: 727204

African (AFR) AF: 0.794 AC: 26576 AN: 33480

American (AMR) AF: 0.303 AC: 13563 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.588 AC: 15373 AN: 26132

East Asian (EAS) AF: 0.170 AC: 6765 AN: 39698

South Asian (SAS) AF: 0.487 AC: 42043 AN: 86258

European-Finnish (FIN) AF: 0.353 AC: 18877 AN: 53414

Middle Eastern (MID) AF: 0.570 AC: 3290 AN: 5768

European-Non Finnish (NFE) AF: 0.467 AC: 519073 AN: 1111932

Other (OTH) AF: 0.491 AC: 29653 AN: 60390

GnomAD4 genome AF: 0.538 AC: 81813 AN: 152080 Hom.: 24222 Cov.: 32 AF XY: 0.528 AC XY: 39268 AN XY: 74350

African (AFR) AF: 0.783 AC: 32471 AN: 41488

American (AMR) AF: 0.445 AC: 6803 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.592 AC: 2055 AN: 3470

East Asian (EAS) AF: 0.181 AC: 939 AN: 5178

South Asian (SAS) AF: 0.471 AC: 2273 AN: 4822

European-Finnish (FIN) AF: 0.349 AC: 3682 AN: 10564

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.469 AC: 31853 AN: 67960

Other (OTH) AF: 0.550 AC: 1161 AN: 2112

Alfa AF: 0.504 Hom.: 31854

Bravo AF: 0.550

Asia WGS AF: 0.426 AC: 1486 AN: 3478

EpiCase AF: 0.490

EpiControl AF: 0.506

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.3
DANN	Benign	0.46
PhyloP100		1.6
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10748; hg19: chr16-53504721; COSMIC: COSV50877123; COSMIC: COSV50877123;