rs587776650

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1PS3PP5_Very_Strong

The NM_002485.5(NBN):c.657_661delACAAA(p.Lys219AsnfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000225 in 1,613,090 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000218835: Experimental studies have shown that this premature translational stop signal affects NBN function (PMID:16033915, 22131123, 22941933)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. K219K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

NBN
NM_002485.5 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:45U:1O:4

Conservation

PhyloP100: 2.47

Publications

88 publications found

Variant links:

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

NBN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 20 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000218835: Experimental studies have shown that this premature translational stop signal affects NBN function (PMID: 16033915, 22131123, 22941933).; SCV001365920: "In vitro functional studies support an impact on protein function and show that this variant leads to the production of an abnormal protein product." (Maser 2001, Dzikiewicz-Krawczyk 2012); SCV000183792: "However, functional studies have indicated that this alteration may partially escape nonsense-mediated decay and produce a protein with some residual function (Maser RS et al. Nat Genet, 2001 Apr;27:417-21)."; SCV000821748: Experimental studies propose that this deletion encodes a partially functional protein that diminishes the severity of the NBS phenotype (PMID: 11279524).; SCV000889554: Functional studies have shown that this variant results in two proteins, the N-terminal p26 fragment and the p70 fragment produced from an internal initiation codon at position p.221 that lacks the N-terminal portion (PMID: 11279524 (2001), 25485873 (2014)). Another study has shown that the variant caused increased chromosomal instability in homozygous cells (PMID: 22131123 (2012)).; SCV001160103: However, functional studies show two in-frame start codons created by the frameshift that can generate truncated NBN proteins with partial functionality (Lins 2009, Maser 2001).; SCV001553205: Functional studies have reported that the variant leads to two truncated fragments, p26 and p70 nibrin, and the translation of a short N-terminal protein with FHA/BRCT domains, therefore maintaining some function of the full-length NBS1 protein (Dzikiewicz-Krawczyk 2008, Cilli 2014).; SCV000806448: Functionally, it has been hypothesized to be a hypomorph, which results in a truncated protein with residual activity of the full-length NBN protein (Maser et al. 2001. PubMed ID: 11279524; Dzikiewicz-Krawczyk et al. 2011. PubMed ID: 22131123).

PP5

Variant 8-89971213-ATTTGT-A is Pathogenic according to our data. Variant chr8-89971213-ATTTGT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NBN	NM_002485.5	MANE Select	c.657_661delACAAA	p.Lys219AsnfsTer16	frameshift	Exon 6 of 16	NP_002476.2
NBN	NM_001024688.3		c.411_415delACAAA	p.Lys137AsnfsTer16	frameshift	Exon 7 of 17	NP_001019859.1	A0A0C4DG07
NBN	NM_001440379.1		c.411_415delACAAA	p.Lys137AsnfsTer16	frameshift	Exon 6 of 16	NP_001427308.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NBN	ENST00000265433.8	TSL:1 MANE Select	c.657_661delACAAA	p.Lys219AsnfsTer16	frameshift	Exon 6 of 16	ENSP00000265433.4	O60934
NBN	ENST00000697309.1		c.657_661delACAAA	p.Lys219AsnfsTer16	frameshift	Exon 6 of 15	ENSP00000513244.1	A0A8V8TKY5
NBN	ENST00000697293.1		c.657_661delACAAA	p.Lys219AsnfsTer16	frameshift	Exon 6 of 17	ENSP00000513230.1	A0A8V8TM80

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000191

AC:

AN:

250742

AF XY:

0.000184

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000926

Gnomad NFE exome

AF:

0.000388

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000228

AC:

333

AN:

1460906

Hom.:

AF XY:

0.000239

AC XY:

174

AN XY:

726760

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33426

American (AMR)

AF:

0.0000224

AC:

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39594

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.0000938

AC:

AN:

53318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000285

AC:

317

AN:

1111458

Other (OTH)

AF:

0.000149

AC:

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.417

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000197

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000397

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000364

Hom.:

Bravo

AF:

0.000219

EpiCase

AF:

0.000600

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Microcephaly, normal intelligence and immunodeficiency (21)

not provided (10)

Hereditary cancer-predisposing syndrome (6)

Aplastic anemia (1)

Aplastic anemia;C0023449:Acute lymphoid leukemia;C0398791:Microcephaly, normal intelligence and immunodeficiency (1)

Breast and/or ovarian cancer (1)

Breast carcinoma (1)

Breast-ovarian cancer, familial, susceptibility to, 1 (2)

Carcinoma of pancreas (1)

Familial prostate cancer (1)

Hepatocellular carcinoma (1)

Lissencephaly;C4551563:Microcephaly (1)

Malignant tumor of breast (1)

NBN-related disorder (1)

Familial cancer of breast;C0398791:Microcephaly, normal intelligence and immunodeficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.5

Mutation Taster

=3/197

disease causing (fs/PTC)

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over