8-89984546-G-T

Position:

• chr8-89984546-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002485.5(NBN):​c.16C>A​(p.Pro6Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.92

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBN	NM_002485.5	c.16C>A	p.Pro6Thr	missense_variant	1/16	ENST00000265433.8	NP_002476.2
NBN	XM_011517046.2	c.16C>A	p.Pro6Thr	missense_variant	1/11		XP_011515348.1
NBN	XM_047421796.1	c.16C>A	p.Pro6Thr	missense_variant	1/10		XP_047277752.1
NBN	NM_001024688.3	c.-281C>A		5_prime_UTR_variant	1/17		NP_001019859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.16C>A	p.Pro6Thr	missense_variant	1/16	1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 06, 2022

This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 6 of the NBN protein (p.Pro6Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 848461). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.015
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Pathogenic	3.0	M;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.3	N;D
REVEL	Benign	0.27
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.020	D;D
Polyphen		0.99	D;.
Vest4		0.53
MutPred		0.63		Gain of MoRF binding (P = 0.0425);Gain of MoRF binding (P = 0.0425);
MVP		0.73
MPC		0.29
ClinPred		0.95	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.18
gMVP		0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs730881859; hg19: chr8-90996774;