chr8-89964502-C-T

Variant names:

• chr8-89964502-C-T
• rs749857140
• NM_002485.5:c.902G>A

Variant summary

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

The NM_002485.5(NBN):​c.902G>A​(p.Gly301Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,437,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G301V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.52
• Publications: 1 publications found

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]

NBN Gene-Disease associations (from GenCC):

• Nijmegen breakage syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Orphanet, ClinGen
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• idiopathic aplastic anemia

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

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=0.23307592).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002485.5. 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
	NBN	NM_002485.5	MANE Select	c.902G>A	p.Gly301Asp	missense	Exon 8 of 16	NP_002476.2
	NBN	NM_001024688.3		c.656G>A	p.Gly219Asp	missense	Exon 9 of 17	NP_001019859.1	A0A0C4DG07
	NBN	NM_001440379.1		c.656G>A	p.Gly219Asp	missense	Exon 8 of 16	NP_001427308.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	ENST00000265433.8	TSL:1 MANE Select	c.902G>A	p.Gly301Asp	missense	Exon 8 of 16	ENSP00000265433.4	O60934
	NBN	ENST00000697309.1		c.902G>A	p.Gly301Asp	missense	Exon 8 of 15	ENSP00000513244.1	A0A8V8TKY5
	NBN	ENST00000697293.1		c.902G>A	p.Gly301Asp	missense	Exon 8 of 17	ENSP00000513230.1	A0A8V8TM80

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251026 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1437560 Hom.: 0 Cov.: 28 AF XY: 0.00000140 AC XY: 1 AN XY: 716842

African (AFR) AF: 0.00 AC: 0 AN: 32868

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26006

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39512

South Asian (SAS) AF: 0.00 AC: 0 AN: 85776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 9.17e-7 AC: 1 AN: 1090108

Other (OTH) AF: 0.00 AC: 0 AN: 59538

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000330 AC: 4

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Microcephaly, normal intelligence and immunodeficiency (3)
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T
Eigen	Benign	0.064
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.5
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.21
Sift	Benign	0.042	D
Sift4G	Benign	0.17	T
Polyphen		0.26	B
Vest4		0.40
MutPred		0.65		Gain of relative solvent accessibility (P = 0.0215)
MVP		0.80
MPC		0.10
ClinPred		0.23	T
GERP RS		4.7
Varity_R		0.18
gMVP		0.63
Mutation Taster		=77/23	polymorphism

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: rs749857140; hg19: chr8-90976730;