chr16-53447098-A-G

Variant names:

• chr16-53447098-A-G
• rs17800727
• NM_005611.4:c.629A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005611.4(RBL2):​c.629A>G​(p.Tyr210Cys) variant causes a missense change. The variant allele was found at a frequency of 0.26 in 1,530,708 control chromosomes in the GnomAD database, including 58,385 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 0.21 (4358 hom., cov: 32)
  • Exomes 𝑓: 0.27 (54027 hom.)
• Consequence: RBL2 NM_005611.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.10
• Publications: 36 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017870069).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005611.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBL2	NM_005611.4	MANE Select	c.629A>G	p.Tyr210Cys	missense	Exon 4 of 22	NP_005602.3
	RBL2	NM_001323608.2		c.629A>G	p.Tyr210Cys	missense	Exon 4 of 23	NP_001310537.1
	RBL2	NM_001323609.2		c.629A>G	p.Tyr210Cys	missense	Exon 4 of 21	NP_001310538.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBL2	ENST00000262133.11	TSL:1 MANE Select	c.629A>G	p.Tyr210Cys	missense	Exon 4 of 22	ENSP00000262133.6
	RBL2	ENST00000379935.8	TSL:1	n.206A>G		non_coding_transcript_exon	Exon 2 of 21
	RBL2	ENST00000544405.6	TSL:2	c.407A>G	p.Tyr136Cys	missense	Exon 4 of 15	ENSP00000443744.2

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31270 AN: 151752 Hom.: 4359 Cov.: 32

Gnomad AFR AF: 0.0524

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0982

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.306

Gnomad OTH AF: 0.245

GnomAD2 exomes AF: 0.212 AC: 50257 AN: 236672 AF XY: 0.218

Gnomad AFR exome AF: 0.0432

Gnomad AMR exome AF: 0.146

Gnomad ASJ exome AF: 0.288

Gnomad EAS exome AF: 0.000411

Gnomad FIN exome AF: 0.238

Gnomad NFE exome AF: 0.302

Gnomad OTH exome AF: 0.250

GnomAD4 exome AF: 0.266 AC: 366938 AN: 1378840 Hom.: 54027 Cov.: 24 AF XY: 0.264 AC XY: 182106 AN XY: 689272

African (AFR) AF: 0.0418 AC: 1311 AN: 31344

American (AMR) AF: 0.157 AC: 6504 AN: 41442

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 7277 AN: 25276

East Asian (EAS) AF: 0.000310 AC: 12 AN: 38720

South Asian (SAS) AF: 0.109 AC: 8812 AN: 80826

European-Finnish (FIN) AF: 0.249 AC: 13152 AN: 52780

Middle Eastern (MID) AF: 0.254 AC: 1392 AN: 5480

European-Non Finnish (NFE) AF: 0.301 AC: 314236 AN: 1045538

Other (OTH) AF: 0.248 AC: 14242 AN: 57434

GnomAD4 genome AF: 0.206 AC: 31261 AN: 151868 Hom.: 4358 Cov.: 32 AF XY: 0.202 AC XY: 14980 AN XY: 74216

African (AFR) AF: 0.0522 AC: 2163 AN: 41442

American (AMR) AF: 0.231 AC: 3527 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 985 AN: 3464

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5172

South Asian (SAS) AF: 0.0981 AC: 473 AN: 4822

European-Finnish (FIN) AF: 0.237 AC: 2480 AN: 10458

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.306 AC: 20794 AN: 67958

Other (OTH) AF: 0.241 AC: 507 AN: 2100

Alfa AF: 0.275 Hom.: 14410

Bravo AF: 0.198

TwinsUK AF: 0.298 AC: 1106

ALSPAC AF: 0.289 AC: 1113

ESP6500AA AF: 0.0530 AC: 233

ESP6500EA AF: 0.308 AC: 2647

ExAC AF: 0.214 AC: 26007

Asia WGS AF: 0.0550 AC: 191 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.30	N
PhyloP100		6.1
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.30
Sift	Benign	0.26	T
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.63
MPC		0.88
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.22
gMVP		0.36
Mutation Taster		=89/11	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17800727; hg19: chr16-53481010; COSMIC: COSV50883543; COSMIC: COSV50883543;