chr8-89978293-T-C

Variant names:

• chr8-89978293-T-C
• rs61754966
• NM_002485.5:c.511A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002485.5(NBN):​c.511A>G​(p.Ile171Val) variant causes a missense change. The variant allele was found at a frequency of 0.00115 in 1,593,902 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I171L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (5 hom.)
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:17 B:10 O:2
• Conservation: PhyloP100: 4.37
• Publications: 97 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.037225217).
• BP6: Variant 8-89978293-T-C is Benign according to our data. Variant chr8-89978293-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 6946.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00139 (212/152314) while in subpopulation NFE AF = 0.00254 (173/68022). AF 95% confidence interval is 0.00223. There are 1 homozygotes in GnomAd4. There are 107 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR,AD gene

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.511A>G	p.Ile171Val	missense	Exon 5 of 16	NP_002476.2
	NBN	NM_001024688.3		c.265A>G	p.Ile89Val	missense	Exon 6 of 17	NP_001019859.1
	NBN	NM_001440379.1		c.265A>G	p.Ile89Val	missense	Exon 5 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.511A>G	p.Ile171Val	missense	Exon 5 of 16	ENSP00000265433.4
	NBN	ENST00000697309.1		c.511A>G	p.Ile171Val	missense	Exon 5 of 15	ENSP00000513244.1
	NBN	ENST00000697293.1		c.511A>G	p.Ile171Val	missense	Exon 5 of 17	ENSP00000513230.1

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 212 AN: 152196 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00254

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00120 AC: 301 AN: 251288 AF XY: 0.00117

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00152

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00196

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.00112 AC: 1618 AN: 1441588 Hom.: 5 Cov.: 28 AF XY: 0.00114 AC XY: 821 AN XY: 718462

African (AFR) AF: 0.0000909 AC: 3 AN: 33000

American (AMR) AF: 0.000336 AC: 15 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.000231 AC: 6 AN: 26004

East Asian (EAS) AF: 0.00327 AC: 129 AN: 39478

South Asian (SAS) AF: 0.0000350 AC: 3 AN: 85778

European-Finnish (FIN) AF: 0.00157 AC: 84 AN: 53402

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5732

European-Non Finnish (NFE) AF: 0.00121 AC: 1325 AN: 1093770

Other (OTH) AF: 0.000871 AC: 52 AN: 59726

GnomAD4 genome AF: 0.00139 AC: 212 AN: 152314 Hom.: 1 Cov.: 33 AF XY: 0.00144 AC XY: 107 AN XY: 74472

African (AFR) AF: 0.000265 AC: 11 AN: 41566

American (AMR) AF: 0.000327 AC: 5 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00173 AC: 9 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00254 AC: 173 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00183 Hom.: 2

Bravo AF: 0.000907

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.00139 AC: 169

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.000927

EpiControl AF: 0.00119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	3	not provided (7)
-	3	2	Hereditary cancer-predisposing syndrome (5)
-	3	1	Microcephaly, normal intelligence and immunodeficiency (4)
-	1	2	not specified (4)
-	1	-	Acute lymphoid leukemia (1)
1	-	-	Aplastic anemia (1)
-	1	-	Breast carcinoma (1)
-	1	-	Carcinoma of colon (1)
-	1	-	Diffuse midline glioma, H3 K27-altered (1)
-	1	-	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Hereditary cancer (1)
-	-	1	NBN-related disorder (1)
-	1	-	Pediatric high-grade glioma (1)
-	-	-	Leukemia, acute lymphoblastic, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		4.4
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.80	N
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.40
MVP		0.68
MPC		0.087
ClinPred		0.11	T
GERP RS		4.8
Varity_R		0.39
gMVP		0.53
Mutation Taster		=16/84	disease causing

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: rs61754966; hg19: chr8-90990521; COSMIC: COSV104545444;