chr16-53470809-T-G

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_005611.4(RBL2):​c.2590T>G​(p.Leu864Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RBL2 NM_005611.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.64
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBL2	NM_005611.4	MANE Select	c.2590T>G	p.Leu864Val	missense	Exon 17 of 22	NP_005602.3
	RBL2	NM_001323608.2		c.2590T>G	p.Leu864Val	missense	Exon 17 of 23	NP_001310537.1	Q08999-1
	RBL2	NM_001323609.2		c.2590T>G	p.Leu864Val	missense	Exon 17 of 21	NP_001310538.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RBL2	ENST00000262133.11	TSL:1 MANE Select	c.2590T>G	p.Leu864Val	missense	Exon 17 of 22	ENSP00000262133.6	Q08999-1
	RBL2	ENST00000379935.8	TSL:1	n.2289T>G		non_coding_transcript_exon	Exon 16 of 21
	RBL2	ENST00000894791.1		c.2590T>G	p.Leu864Val	missense	Exon 17 of 22	ENSP00000564850.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 55 AF XY: 0.00 AC XY: 0 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	1.7	L
PhyloP100		1.6
PrimateAI	Uncertain	0.79	T
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.70
Sift	Benign	0.079	T
Sift4G	Benign	0.097	T
Polyphen		1.0	D
Vest4		0.75
MutPred		0.70		Loss of stability (P = 0.0838)
MVP		0.91
MPC		0.82
ClinPred		0.87	D
GERP RS		2.2
Varity_R		0.22
gMVP		0.50

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;