8-89943367-C-G

Variant names:

• chr8-89943367-C-G
• rs786201965
• NM_002485.5:c.2071-1G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1_Moderate PS3 PM2 PP5

The NM_002485.5(NBN):​c.2071-1G>C variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000138 in 1,448,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000830406: RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. Studies have shown that disruption of this splice site results in skipping of exon 14, but is expected to preserve the integrity of the reading-frame (internal data).".

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NBN NM_002485.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:8 U:1
• Conservation: PhyloP100: 5.17
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Orphanet, ClinGen
• 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: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.050331127 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000830406: RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. Studies have shown that disruption of this splice site results in skipping of exon 14, but is expected to preserve the integrity of the reading-frame (internal data).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-89943367-C-G is Pathogenic according to our data. Variant chr8-89943367-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 185152.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	NM_002485.5	MANE Select	c.2071-1G>C		splice_acceptor intron	N/A	NP_002476.2
	NBN	NM_001024688.3		c.1825-1G>C		splice_acceptor intron	N/A	NP_001019859.1	A0A0C4DG07
	NBN	NM_001440379.1		c.1825-1G>C		splice_acceptor intron	N/A	NP_001427308.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	ENST00000265433.8	TSL:1 MANE Select	c.2071-1G>C		splice_acceptor intron	N/A	ENSP00000265433.4	O60934
	NBN	ENST00000697309.1		c.2071-1G>C		splice_acceptor intron	N/A	ENSP00000513244.1	A0A8V8TKY5
	NBN	ENST00000697293.1		c.2071-1G>C		splice_acceptor intron	N/A	ENSP00000513230.1	A0A8V8TM80

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1448480 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 721460

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33040

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26044

East Asian (EAS) AF: 0.00 AC: 0 AN: 39570

South Asian (SAS) AF: 0.00 AC: 0 AN: 86002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1100158

Other (OTH) AF: 0.0000167 AC: 1 AN: 59936

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
3	-	-	Microcephaly, normal intelligence and immunodeficiency (3)
2	1	-	not provided (3)
1	-	-	Aplastic anemia (1)
1	-	-	Aplastic anemia;C0023449:Acute lymphoid leukemia;C0398791:Microcephaly, normal intelligence and immunodeficiency (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		5.2
GERP RS		5.6
Mutation Taster		=8/92	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AL_spliceai		1.0		Position offset: -1

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

Other links and lift over

dbSNP: rs786201965; hg19: chr8-90955595;