rs587781547

Variant names:

• chr8-89946285-T-C
• rs587781547
• NM_002485.5:c.1925A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_002485.5(NBN):​c.1925A>G​(p.Lys642Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000133 in 1,430,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. K642E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 0.0950
• Publications: 4 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04663956).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	NM_002485.5	MANE Select	c.1925A>G	p.Lys642Arg	missense	Exon 13 of 16	NP_002476.2
	NBN	NM_001024688.3		c.1679A>G	p.Lys560Arg	missense	Exon 14 of 17	NP_001019859.1
	NBN	NM_001440379.1		c.1679A>G	p.Lys560Arg	missense	Exon 13 of 16	NP_001427308.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	ENST00000265433.8	TSL:1 MANE Select	c.1925A>G	p.Lys642Arg	missense	Exon 13 of 16	ENSP00000265433.4
	NBN	ENST00000697309.1		c.1925A>G	p.Lys642Arg	missense	Exon 13 of 15	ENSP00000513244.1
	NBN	ENST00000697293.1		c.1925A>G	p.Lys642Arg	missense	Exon 13 of 17	ENSP00000513230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251052 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000133 AC: 19 AN: 1430002 Hom.: 0 Cov.: 32 AF XY: 0.0000126 AC XY: 9 AN XY: 713068

African (AFR) AF: 0.0000610 AC: 2 AN: 32768

American (AMR) AF: 0.0000672 AC: 3 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25928

East Asian (EAS) AF: 0.00 AC: 0 AN: 39354

South Asian (SAS) AF: 0.00 AC: 0 AN: 85480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.0000120 AC: 13 AN: 1083434

Other (OTH) AF: 0.0000168 AC: 1 AN: 59418

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	Microcephaly, normal intelligence and immunodeficiency (4)
-	1	-	Aplastic anemia;C0023449:Acute lymphoid leukemia;C0398791:Microcephaly, normal intelligence and immunodeficiency (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	NBN-related disorder (1)
-	1	-	not specified (1)
-	1	-	Prostate cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.8
DANN	Benign	0.91
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.095
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.012
Sift	Benign	0.17	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.029
MutPred		0.28		Loss of ubiquitination at K642 (P = 2e-04)
MVP		0.52
MPC		0.057
ClinPred		0.039	T
GERP RS		-2.3
Varity_R		0.025
gMVP		0.097
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs587781547; hg19: chr8-90958513; COSMIC: COSV55372637;