8-89984528-C-G

Variant names:

• chr8-89984528-C-G
• rs878854511
• NM_002485.5:c.34G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_002485.5(NBN):​c.34G>C​(p.Gly12Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G12E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.26
• Publications: 1 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

ENSG00000309953 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060400397).
• BP6: Variant 8-89984528-C-G is Benign according to our data. Variant chr8-89984528-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 630431.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5	c.34G>C	p.Gly12Arg	missense_variant	Exon 1 of 16	ENST00000265433.8	NP_002476.2
NBN	XM_011517046.2	c.34G>C	p.Gly12Arg	missense_variant	Exon 1 of 11		XP_011515348.1
NBN	XM_047421796.1	c.34G>C	p.Gly12Arg	missense_variant	Exon 1 of 10		XP_047277752.1
NBN	NM_001024688.3	c.-263G>C		5_prime_UTR_variant	Exon 1 of 17		NP_001019859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.34G>C	p.Gly12Arg	missense_variant	Exon 1 of 16	1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:1

Apr 17, 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	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	13
DANN	Benign	0.76
DEOGEN2	Benign	0.048	T;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.00027	N
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.060	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.38	N;.
PhyloP100		1.3
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.38	N;N
REVEL	Benign	0.029
Sift	Benign	0.19	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.0020	B;.
Vest4		0.14
MutPred		0.36		Gain of solvent accessibility (P = 0.0037);Gain of solvent accessibility (P = 0.0037);
MVP		0.41
MPC		0.079
ClinPred		0.12	T
GERP RS		2.8
PromoterAI		0.060	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.038
gMVP		0.54
Mutation Taster		=82/18	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: rs878854511; hg19: chr8-90996756;