chr8-89936938-G-C

Variant names:

• chr8-89936938-G-C
• rs13312970
• NM_002485.5:c.2234+88C>G

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.2234+88C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0442 in 1,063,834 control chromosomes in the GnomAD database, including 1,621 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (433 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1188 hom.)
• Consequence: NBN NM_002485.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.771
• Publications: 7 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=-0.89).
• BP6: Variant 8-89936938-G-C is Benign according to our data. Variant chr8-89936938-G-C is described in ClinVar as Benign. ClinVar VariationId is 1232508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5	c.2234+88C>G		intron_variant	Intron 15 of 15	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.2234+88C>G		intron_variant	Intron 15 of 15	1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes AF: 0.0600 AC: 9124 AN: 152070 Hom.: 427 Cov.: 32

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0577

Gnomad ASJ AF: 0.0398

Gnomad EAS AF: 0.0553

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.00933

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0299

Gnomad OTH AF: 0.0602

GnomAD4 exome AF: 0.0415 AC: 37847 AN: 911646 Hom.: 1188 AF XY: 0.0432 AC XY: 20465 AN XY: 473746

African (AFR) AF: 0.122 AC: 2747 AN: 22556

American (AMR) AF: 0.0492 AC: 2032 AN: 41316

Ashkenazi Jewish (ASJ) AF: 0.0433 AC: 962 AN: 22234

East Asian (EAS) AF: 0.0689 AC: 2501 AN: 36280

South Asian (SAS) AF: 0.0938 AC: 6829 AN: 72800

European-Finnish (FIN) AF: 0.00825 AC: 351 AN: 42564

Middle Eastern (MID) AF: 0.0577 AC: 183 AN: 3172

European-Non Finnish (NFE) AF: 0.0323 AC: 20330 AN: 628914

Other (OTH) AF: 0.0457 AC: 1912 AN: 41810

GnomAD4 genome AF: 0.0601 AC: 9147 AN: 152188 Hom.: 433 Cov.: 32 AF XY: 0.0593 AC XY: 4416 AN XY: 74436

African (AFR) AF: 0.122 AC: 5060 AN: 41490

American (AMR) AF: 0.0577 AC: 882 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0398 AC: 138 AN: 3468

East Asian (EAS) AF: 0.0556 AC: 288 AN: 5180

South Asian (SAS) AF: 0.102 AC: 491 AN: 4822

European-Finnish (FIN) AF: 0.00933 AC: 99 AN: 10614

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0298 AC: 2029 AN: 67998

Other (OTH) AF: 0.0667 AC: 141 AN: 2114

Alfa AF: 0.0455 Hom.: 38

Bravo AF: 0.0652

Asia WGS AF: 0.109 AC: 383 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Benign:1

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

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	-0.89
CADD	Benign	3.9
DANN	Benign	0.44
PhyloP100		0.77
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: rs13312970; hg19: chr8-90949166;