NM_002485.5:c.818C>G

Variant names:

• chr8-89970442-G-C
• rs1554563912
• NM_002485.5:c.818C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002485.5(NBN):​c.818C>G​(p.Thr273Arg) 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. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T273I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.0920
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07940242).

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.818C>G	p.Thr273Arg	missense	Exon 7 of 16	NP_002476.2
	NBN	NM_001024688.3		c.572C>G	p.Thr191Arg	missense	Exon 8 of 17	NP_001019859.1
	NBN	NM_001440379.1		c.572C>G	p.Thr191Arg	missense	Exon 7 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.818C>G	p.Thr273Arg	missense	Exon 7 of 16	ENSP00000265433.4
	NBN	ENST00000697309.1		c.818C>G	p.Thr273Arg	missense	Exon 7 of 15	ENSP00000513244.1
	NBN	ENST00000697293.1		c.818C>G	p.Thr273Arg	missense	Exon 7 of 17	ENSP00000513230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Uncertain significance and reported on 11-25-2019 by Lab or GTR ID Credit Valley Hospital Department of Laboratory Medicine. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	10
DANN	Benign	0.74
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.092
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.10
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.25	B
Vest4		0.34
MutPred		0.41		Loss of helix (P = 0.0093)
MVP		0.42
MPC		0.085
ClinPred		0.26	T
GERP RS		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.68
Mutation Taster		=96/4	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: rs1554563912; hg19: chr8-90982670;