8-89946290-A-T

Variant names:

• chr8-89946290-A-T
• rs1554556602
• NM_002485.5:c.1920T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002485.5(NBN):​c.1920T>A​(p.Asn640Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000007 in 1,429,222 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. N640I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.35
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06449571).

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.1920T>A	p.Asn640Lys	missense	Exon 13 of 16	NP_002476.2
	NBN	NM_001024688.3		c.1674T>A	p.Asn558Lys	missense	Exon 14 of 17	NP_001019859.1
	NBN	NM_001440379.1		c.1674T>A	p.Asn558Lys	missense	Exon 13 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.1920T>A	p.Asn640Lys	missense	Exon 13 of 16	ENSP00000265433.4
	NBN	ENST00000697309.1		c.1920T>A	p.Asn640Lys	missense	Exon 13 of 15	ENSP00000513244.1
	NBN	ENST00000697293.1		c.1920T>A	p.Asn640Lys	missense	Exon 13 of 17	ENSP00000513230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1429222 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 712710

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000305 AC: 1 AN: 32744

American (AMR) AF: 0.00 AC: 0 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25930

East Asian (EAS) AF: 0.00 AC: 0 AN: 39350

South Asian (SAS) AF: 0.00 AC: 0 AN: 85470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1082750

Other (OTH) AF: 0.00 AC: 0 AN: 59376

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	14
DANN	Benign	0.64
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.4
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.037
Sift	Benign	0.33	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.072
MutPred		0.20		Gain of ubiquitination at N640 (P = 0.0069)
MVP		0.69
MPC		0.077
ClinPred		0.053	T
GERP RS		1.9
Varity_R		0.050
gMVP		0.085
Mutation Taster		=96/4	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: rs1554556602; hg19: chr8-90958518;