8-89984539-G-C

Position:

• chr8-89984539-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002485.5(NBN):​c.23C>G​(p.Ala8Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.267838).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBN	NM_002485.5	c.23C>G	p.Ala8Gly	missense_variant	1/16	ENST00000265433.8	NP_002476.2
NBN	XM_011517046.2	c.23C>G	p.Ala8Gly	missense_variant	1/11		XP_011515348.1
NBN	XM_047421796.1	c.23C>G	p.Ala8Gly	missense_variant	1/10		XP_047277752.1
NBN	NM_001024688.3	c.-274C>G		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.23C>G	p.Ala8Gly	missense_variant	1/16	1	NM_002485.5	ENSP00000265433	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460784 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726750

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

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

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T;.
Eigen	Benign	-0.087
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.0059	N
LIST_S2	Benign	0.57	T;T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	0.96	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.11
Sift	Benign	0.069	T;T
Sift4G	Benign	0.097	T;T
Polyphen		0.99	D;.
Vest4		0.12
MutPred		0.59		Loss of stability (P = 0.0453);Loss of stability (P = 0.0453);
MVP		0.58
MPC		0.074
ClinPred		0.67	D
GERP RS		3.7
Varity_R		0.068
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-90996767;