chr8-143836003-G-C

Variant names:

• chr8-143836003-G-C
• rs782670268
• NM_178564.4:c.1345C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_178564.4(NRBP2):​c.1345C>G​(p.Arg449Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000211 in 1,424,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R449Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NRBP2 NM_178564.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.43
• Publications: 0 publications found

Genes affected

NRBP2 (HGNC:19339): (nuclear receptor binding protein 2) Predicted to enable protein serine/threonine kinase activity. Involved in negative regulation of macroautophagy. Predicted to be active in cytoplasm and endomembrane system. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22042689).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRBP2	NM_178564.4	c.1345C>G	p.Arg449Gly	missense_variant	Exon 16 of 18	ENST00000442628.7	NP_848659.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRBP2	ENST00000442628.7	c.1345C>G	p.Arg449Gly	missense_variant	Exon 16 of 18	2	NM_178564.4	ENSP00000414055.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1424992 Hom.: 0 Cov.: 34 AF XY: 0.00000283 AC XY: 2 AN XY: 705584

African (AFR) AF: 0.00 AC: 0 AN: 31780

American (AMR) AF: 0.00 AC: 0 AN: 41438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24130

East Asian (EAS) AF: 0.00 AC: 0 AN: 38688

South Asian (SAS) AF: 0.00 AC: 0 AN: 82432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5622

European-Non Finnish (NFE) AF: 0.00000274 AC: 3 AN: 1093634

Other (OTH) AF: 0.00 AC: 0 AN: 58724

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.4
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.11
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.010	D
Polyphen		0.0010	B
Vest4		0.52
MutPred		0.46		Gain of catalytic residue at Q453 (P = 0.0394);
MVP		0.22
MPC		0.22
ClinPred		0.94	D
GERP RS		-6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.27
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs782670268; hg19: chr8-144918173;