8-89978299-G-T

Position:

• chr8-89978299-G-T

Variant summary

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

The NM_002485.5(NBN):​c.505C>A​(p.Arg169Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000417 in 1,437,170 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R169C) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.214

Genes affected

NBN (HGNC:7652): (nibrin) Mutations in this gene are associated with Nijmegen breakage syndrome, an autosomal recessive chromosomal instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. The encoded protein is a member of the MRE11/RAD50 double-strand break repair complex which consists of 5 proteins. This gene product is thought to be involved in DNA double-strand break repair and DNA damage-induced checkpoint activation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBN	NM_002485.5	c.505C>A	p.Arg169Ser	missense_variant	5/16	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.505C>A	p.Arg169Ser	missense_variant	5/16	1	NM_002485.5	ENSP00000265433	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251246 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135824

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000417 AC: 6 AN: 1437170 Hom.: 0 Cov.: 28 AF XY: 0.00000279 AC XY: 2 AN XY: 716376

Gnomad4 AFR exome AF: 0.00

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: 0.00000551

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000130 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T;T;.;.
Eigen	Benign	0.0046
Eigen_PC	Benign	-0.089
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.93	D;T;D;D
M_CAP	Benign	0.061	D
MetaRNN	Uncertain	0.44	T;T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.2	M;.;.;.
MutationTaster	Benign	0.56	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.2	N;N;N;D
REVEL	Uncertain	0.30
Sift	Benign	0.032	D;D;D;D
Sift4G	Uncertain	0.010	D;D;.;D
Polyphen		0.97	D;.;.;.
Vest4		0.61
MutPred		0.61		Gain of glycosylation at R169 (P = 0.0759);.;.;.;
MVP		0.82
MPC		0.18
ClinPred		0.74	D
GERP RS		-2.5
Varity_R		0.12
gMVP		0.78

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: rs182756889; hg19: chr8-90990527;