rs1280333137

Variant names:

• chr8-89964503-C-G
• rs1280333137
• NM_002485.5:c.901G>C

Your query was ambiguous. Multiple possible variants found:

• chr8-89964503-C-G
• chr8-89964503-C-T

Variant summary

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

The NM_002485.5(NBN):​c.901G>C​(p.Gly301Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,436,964 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G301V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.267
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.901G>C	p.Gly301Arg	missense	Exon 8 of 16	NP_002476.2
	NBN	NM_001024688.3		c.655G>C	p.Gly219Arg	missense	Exon 9 of 17	NP_001019859.1
	NBN	NM_001440379.1		c.655G>C	p.Gly219Arg	missense	Exon 8 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.901G>C	p.Gly301Arg	missense	Exon 8 of 16	ENSP00000265433.4
	NBN	ENST00000697309.1		c.901G>C	p.Gly301Arg	missense	Exon 8 of 15	ENSP00000513244.1
	NBN	ENST00000697293.1		c.901G>C	p.Gly301Arg	missense	Exon 8 of 17	ENSP00000513230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 250996 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 6.96e-7 AC: 1 AN: 1436964 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 716556

African (AFR) AF: 0.00 AC: 0 AN: 32846

American (AMR) AF: 0.0000224 AC: 1 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25994

East Asian (EAS) AF: 0.00 AC: 0 AN: 39512

South Asian (SAS) AF: 0.00 AC: 0 AN: 85760

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089610

Other (OTH) AF: 0.00 AC: 0 AN: 59520

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Microcephaly, normal intelligence and immunodeficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.27
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.20
Sift	Benign	0.037	D
Sift4G	Uncertain	0.056	T
Polyphen		0.86	P
Vest4		0.51
MutPred		0.68		Gain of solvent accessibility (P = 0.0171)
MVP		0.78
MPC		0.17
ClinPred		0.45	T
GERP RS		4.6
Varity_R		0.085
gMVP		0.67
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: rs1280333137; hg19: chr8-90976731;