8-89953312-G-C

Position:

chr8-89953312-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_002485.5(NBN):c.1777C>G(p.Pro593Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,613,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00057 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

NBN
NM_002485.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:6

Conservation

PhyloP100: 1.59

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 links:

NBN (HGNC:):

NBN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047795773).

BP6

Variant 8-89953312-G-C is Benign according to our data. Variant chr8-89953312-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127862.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=4, Benign=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000566 (86/152068) while in subpopulation AFR AF= 0.00202 (84/41490). AF 95% confidence interval is 0.00168. There are 0 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBN	NM_002485.5 linkuse as main transcript	c.1777C>G	p.Pro593Ala	missense_variant	11/16	ENST00000265433.8	NP_002476.2	O60934

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8 linkuse as main transcript	c.1777C>G	p.Pro593Ala	missense_variant	11/16	1	NM_002485.5	ENSP00000265433.4		O60934

Frequencies

GnomAD3 genomes

AF:

0.000566

AC:

AN:

151950

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00203

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000163

AC:

AN:

250866

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135640

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000568

AC:

AN:

1461134

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

726898

show subpopulations

Gnomad4 AFR exome

AF:

0.00233

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000566

AC:

AN:

152068

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.00202

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000225

Hom.:

Bravo

AF:

0.000740

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000214

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 27, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 18, 2019	Variant summary: NBN c.1777C>G (p.Pro593Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 276572 control chromosomes, predominantly at a frequency of 0.0022 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 17.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Hereditary Breast and Ovarian Cancer phenotype (0.00013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. c.1777C>G has been reported in the literature in individuals affected with Breast and Ovarian Cancer (Haiman_2013, Tung_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.2808_2811delACAA, p.Ala938fsX21), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, 4 classify as VUS while 1 classified as likley benign. Based on the evidence outlined above, the variant was classified as likely benign. -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 08, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history of breast and/or ovarian cancer (Haiman et al., 2013; Tung et al., 2015); This variant is associated with the following publications: (PMID: 23555315, 25186627) -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 21, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 13, 2021	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

NBN-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 17, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.21

T;T;.

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.77

T;T;T

M_CAP

Benign

0.0078

MetaRNN

Benign

0.0048

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.7

L;.;.

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.1

N;N;.

REVEL

Benign

0.038

Sift

Benign

0.13

T;T;.

Sift4G

Benign

0.42

T;T;T

Polyphen

0.025

B;.;.

Vest4

0.19

MVP

0.61

MPC

0.076

ClinPred

0.0064

GERP RS

3.5

Varity_R

0.052

gMVP

0.065

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over