NM_002485.5:c.1397+3C>G

Variant names:

• chr8-89955280-G-C
• rs876660481
• NM_002485.5:c.1397+3C>G

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-3 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -3 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_StrongBP6

The NM_002485.5(NBN):c.1397+3C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000434 (AC=7) in the gnomAD database across 1,612,988 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000132. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NBN NM_002485.5 splice_region, intron
• Scores: Splicing: ADA: 0.00002728
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 0.995
• Publications: 0 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: Natera, Orphanet, G2P, Myriad Women's Health, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• 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
• familial ovarian cancer

  Inheritance: Unknown Classification: LIMITED Submitted by: Natera
• hereditary breast carcinoma

  Inheritance: Unknown, AD Classification: NO_KNOWN Submitted by: Natera, ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Our verdict: Likely_benign. The variant received -3 points.

• PM2: Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000132 — very rare for AD+AR gene (base 0.0001, raised to 0.000225 by highest known P/LP ClinVar AF 0.000225) — PM2 moderate.
• BP4: Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
• BP6: ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_002485.5. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	NM_002485.5	MANE Select	c.1397+3C>G		splice_region intron	N/A	NP_002476.2
	NBN	NM_001024688.3		c.1151+3C>G		splice_region intron	N/A	NP_001019859.1	A0A0C4DG07
	NBN	NM_001440379.1		c.1151+3C>G		splice_region intron	N/A	NP_001427308.1	A0A0C4DG07

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	ENST00000265433.8	TSL:1 MANE Select	c.1397+3C>G		splice_region intron	N/A	ENSP00000265433.4	O60934
	NBN	ENST00000697309.1		c.1397+3C>G		splice_region intron	N/A	ENSP00000513244.1	A0A8V8TKY5
	NBN	ENST00000697293.1		c.1397+3C>G		splice_region intron	N/A	ENSP00000513230.1	A0A8V8TM80

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	0.0000132	2	0	151940	32
GnomAD4 exome	0.00000342	5	0	1461048	32
GnomAD4 genome	0.0000132	2	0	151940	32
TOPMed (Bravo)	0.0000113
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	0.0000524	2	1	38198

Showing 5 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00	0	67850	0.00000750	1	133284

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Microcephaly, normal intelligence and immunodeficiency (3)
-	1	1	Hereditary cancer-predisposing syndrome (2)

Computational Scores

Algorithm	Calibrated prediction	Prediction	Score
AlphaGenome AVI	Benign	-	9.7
BayesDel_noAF	Benign	-	-0.57
CADD	Benign	-	10
DANN	Benign	-	0.58
GPN-Star LLR	N/A	-	-2.8
GPN-Star score	N/A	-	2.8
PhyloP100	Benign	-	0.99

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated prediction	Prediction	Score
dbscSNV1_ADA	Benign	-	0.000027
dbscSNV1_RF	Benign	-	0.028
Pangolin (max)	Benign	-	0.0
SpliceAI score (max)	Benign	- Details are displayed if max score is > 0.2	0.0

Showing 4 of 4 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs876660481;

hg19: chr8-90967508;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar