rs6990969

Variant names:

• chr8-89964177-C-T
• rs6990969
• NM_002485.5:c.994+233G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002485.5(NBN):​c.994+233G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.33 in 152,014 control chromosomes in the GnomAD database, including 8,373 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.33 (8373 hom., cov: 32)
• Consequence: NBN NM_002485.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.51
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 8-89964177-C-T is Benign according to our data. Variant chr8-89964177-C-T is described in ClinVar as Benign. ClinVar VariationId is 1177039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5	c.994+233G>A		intron_variant	Intron 8 of 15	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.994+233G>A		intron_variant	Intron 8 of 15	1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes AF: 0.330 AC: 50151 AN: 151896 Hom.: 8364 Cov.: 32

Gnomad AFR AF: 0.305

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.350

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.353

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.336

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.330 AC: 50185 AN: 152014 Hom.: 8373 Cov.: 32 AF XY: 0.335 AC XY: 24897 AN XY: 74326

African (AFR) AF: 0.305 AC: 12623 AN: 41436

American (AMR) AF: 0.351 AC: 5351 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 1092 AN: 3470

East Asian (EAS) AF: 0.452 AC: 2341 AN: 5180

South Asian (SAS) AF: 0.437 AC: 2110 AN: 4826

European-Finnish (FIN) AF: 0.353 AC: 3722 AN: 10542

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.322 AC: 21901 AN: 67986

Other (OTH) AF: 0.340 AC: 719 AN: 2112

Alfa AF: 0.332 Hom.: 1122

Bravo AF: 0.325

Asia WGS AF: 0.425 AC: 1478 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jun 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.076
DANN	Benign	0.65
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs6990969; hg19: chr8-90976405;