rs201781110

Variant names:

• chr8-89946231-C-A
• rs201781110
• NM_002485.5:c.1979G>T

Your query was ambiguous. Multiple possible variants found:

• chr8-89946231-C-A
• chr8-89946231-C-G
• chr8-89946231-C-T

Variant summary

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

The ENST00000265433.8(NBN):​c.1979G>T​(p.Arg660Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,439,604 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. R660T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NBN ENST00000265433.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.62
• 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: ENST00000265433.8. 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.1979G>T	p.Arg660Ile	missense	Exon 13 of 16	NP_002476.2
	NBN	NM_001024688.3		c.1733G>T	p.Arg578Ile	missense	Exon 14 of 17	NP_001019859.1
	NBN	NM_001440379.1		c.1733G>T	p.Arg578Ile	missense	Exon 13 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.1979G>T	p.Arg660Ile	missense	Exon 13 of 16	ENSP00000265433.4
	NBN	ENST00000697309.1		c.1979G>T	p.Arg660Ile	missense	Exon 13 of 15	ENSP00000513244.1
	NBN	ENST00000697293.1		c.1979G>T	p.Arg660Ile	missense	Exon 13 of 17	ENSP00000513230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1439604 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 717420

African (AFR) AF: 0.00 AC: 0 AN: 32992

American (AMR) AF: 0.00 AC: 0 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25988

East Asian (EAS) AF: 0.00 AC: 0 AN: 39396

South Asian (SAS) AF: 0.00 AC: 0 AN: 85708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 9.16e-7 AC: 1 AN: 1092142

Other (OTH) AF: 0.00 AC: 0 AN: 59678

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Microcephaly, normal intelligence and immunodeficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	0.0065	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	0.012
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.6
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.25
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.67	P
Vest4		0.68
MutPred		0.58		Gain of sheet (P = 0.0016)
MVP		0.72
MPC		0.34
ClinPred		0.95	D
GERP RS		4.8
Varity_R		0.31
gMVP		0.44
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs201781110; hg19: chr8-90958459;