8-89955478-G-T

Variant names:

• chr8-89955478-G-T
• rs104895033
• NM_002485.5:c.1202C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002485.5(NBN):​c.1202C>A​(p.Pro401His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,366 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. P401R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.195
• Publications: 6 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.085010886).

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.1202C>A	p.Pro401His	missense	Exon 10 of 16	NP_002476.2
	NBN	NM_001024688.3		c.956C>A	p.Pro319His	missense	Exon 11 of 17	NP_001019859.1
	NBN	NM_001440379.1		c.956C>A	p.Pro319His	missense	Exon 10 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.1202C>A	p.Pro401His	missense	Exon 10 of 16	ENSP00000265433.4
	NBN	ENST00000697309.1		c.1202C>A	p.Pro401His	missense	Exon 10 of 15	ENSP00000513244.1
	NBN	ENST00000697293.1		c.1202C>A	p.Pro401His	missense	Exon 10 of 17	ENSP00000513230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461366 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 726988

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111644

Other (OTH) AF: 0.00 AC: 0 AN: 60372

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Uncertain:2

Apr 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 401 of the NBN protein (p.Pro401His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 219698). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Nov 07, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1

Oct 12, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted NBN c.1202C>A at the cDNA level, p.Pro401His (P401H) at the protein level, and results in the change of a Proline to a Histidine (CCC>CAC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. NBN Pro401His was not observed in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether NBN Pro401His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

Hereditary cancer-predisposing syndrome Uncertain:1

Apr 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P401H variant (also known as c.1202C>A), located in coding exon 10 of the NBN gene, results from a C to A substitution at nucleotide position 1202. The proline at codon 401 is replaced by histidine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	5.4
DANN	Benign	0.16
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.085	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.20
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.26	N
REVEL	Benign	0.053
Sift	Benign	0.54	T
Sift4G	Benign	0.091	T
Polyphen		0.070	B
Vest4		0.16
MutPred		0.24		Gain of MoRF binding (P = 0.0477)
MVP		0.52
MPC		0.10
ClinPred		0.045	T
GERP RS		-2.9
Varity_R		0.030
gMVP		0.13
Mutation Taster		=90/10	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: rs104895033; hg19: chr8-90967706;