8-89970406-C-G

Variant names:

• chr8-89970406-C-G
• rs863224715
• NM_002485.5:c.854G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP6

The ENST00000265433.8(NBN):​c.854G>C​(p.Cys285Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. C285G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NBN ENST00000265433.8 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.62
• 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: 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.028358102).
• BP6: Variant 8-89970406-C-G is Benign according to our data. Variant chr8-89970406-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 216569.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000265433.8. 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.854G>C	p.Cys285Ser	missense	Exon 7 of 16	NP_002476.2
	NBN	NM_001024688.3		c.608G>C	p.Cys203Ser	missense	Exon 8 of 17	NP_001019859.1
	NBN	NM_001440379.1		c.608G>C	p.Cys203Ser	missense	Exon 7 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.854G>C	p.Cys285Ser	missense	Exon 7 of 16	ENSP00000265433.4
	NBN	ENST00000697309.1		c.854G>C	p.Cys285Ser	missense	Exon 7 of 15	ENSP00000513244.1
	NBN	ENST00000697293.1		c.854G>C	p.Cys285Ser	missense	Exon 7 of 17	ENSP00000513230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	17
DANN	Benign	0.21
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.9	N
PhyloP100		3.6
PrimateAI	Benign	0.32	T
PROVEAN	Benign	2.7	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.078
MutPred		0.46		Gain of disorder (P = 0.0016)
MVP		0.35
MPC		0.081
ClinPred		0.12	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.068
gMVP		0.31
Mutation Taster		=96/4	polymorphism

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: rs863224715; hg19: chr8-90982634;