chr8-89958813-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_002485.5(NBN):c.1036G>C(p.Val346Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V346M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NBN
NM_002485.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 0.679

Publications

0 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: 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

NBN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.02883023).

BP6

Variant 8-89958813-C-G is Benign according to our data. Variant chr8-89958813-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1684941. Variant chr8-89958813-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1684941. Variant chr8-89958813-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1684941. Variant chr8-89958813-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1684941. Variant chr8-89958813-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1684941. Variant chr8-89958813-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1684941. Variant chr8-89958813-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1684941. Variant chr8-89958813-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1684941. Variant chr8-89958813-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1684941. Variant chr8-89958813-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1684941. Variant chr8-89958813-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1684941. Variant chr8-89958813-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1684941. Variant chr8-89958813-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1684941. Variant chr8-89958813-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1684941. Variant chr8-89958813-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1684941. Variant chr8-89958813-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1684941. Variant chr8-89958813-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1684941. Variant chr8-89958813-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1684941. Variant chr8-89958813-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1684941. Variant chr8-89958813-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1684941. Variant chr8-89958813-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1684941. Variant chr8-89958813-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1684941. Variant chr8-89958813-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1684941.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5 link	c.1036G>C	p.Val346Leu	missense_variant	Exon 9 of 16	ENST00000265433.8	NP_002476.2	O60934

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8 link	c.1036G>C	p.Val346Leu	missense_variant	Exon 9 of 16	1	NM_002485.5	ENSP00000265433.4		O60934

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461580

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727128

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111758

Other (OTH)

AF:

0.00

AC:

AN:

60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

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

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 04, 2022

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

May 18, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

8.6

(source)

DANN

Benign

0.14

DEOGEN2

Benign

0.056

T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.031

T;T

M_CAP

Benign

0.0074

MetaRNN

Benign

0.029

T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-2.6

N;.

PhyloP100

0.68

PrimateAI

Benign

0.25

PROVEAN

Benign

0.40

N;N

REVEL

Benign

0.13

Sift

Benign

1.0

T;T

Sift4G

Benign

0.63

T;T

Polyphen

0.0

B;.

Vest4

0.065

MutPred

0.16

Loss of glycosylation at S347 (P = 0.0938);.;

MVP

0.43

MPC

0.066

ClinPred

0.036

GERP RS

3.1

Varity_R

0.020

gMVP

0.15

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over