NM_002485.5:c.*2212G>A

Variant names:

• chr8-89933370-C-T
• rs10464867
• NM_002485.5:c.*2212G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002485.5(NBN):​c.*2212G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0371 in 219,934 control chromosomes in the GnomAD database, including 424 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.033 (224 hom., cov: 32)
  • Exomes 𝑓: 0.046 (200 hom.)
• Consequence: NBN NM_002485.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.410
• Publications: 5 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 8-89933370-C-T is Benign according to our data. Variant chr8-89933370-C-T is described in ClinVar as Benign. ClinVar VariationId is 363891.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	NM_002485.5	MANE Select	c.*2212G>A		3_prime_UTR	Exon 16 of 16	NP_002476.2
	NBN	NM_001024688.3		c.*2212G>A		3_prime_UTR	Exon 17 of 17	NP_001019859.1
	NBN	NM_001440379.1		c.*2212G>A		3_prime_UTR	Exon 16 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.*2212G>A		3_prime_UTR	Exon 16 of 16	ENSP00000265433.4
	NBN	ENST00000396252.6	TSL:5	n.*4350G>A		non_coding_transcript_exon	Exon 19 of 19	ENSP00000379551.2
	NBN	ENST00000494804.2	TSL:3	n.5779G>A		non_coding_transcript_exon	Exon 15 of 15

Frequencies

GnomAD3 genomes AF: 0.0332 AC: 5042 AN: 152094 Hom.: 222 Cov.: 32

Gnomad AFR AF: 0.00517

Gnomad AMI AF: 0.0363

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.171

Gnomad SAS AF: 0.0713

Gnomad FIN AF: 0.0475

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0186

Gnomad OTH AF: 0.0378

GnomAD4 exome AF: 0.0459 AC: 3106 AN: 67722 Hom.: 200 Cov.: 0 AF XY: 0.0457 AC XY: 1435 AN XY: 31398

African (AFR) AF: 0.00546 AC: 17 AN: 3112

American (AMR) AF: 0.118 AC: 239 AN: 2022

Ashkenazi Jewish (ASJ) AF: 0.00717 AC: 31 AN: 4322

East Asian (EAS) AF: 0.192 AC: 1865 AN: 9700

South Asian (SAS) AF: 0.0870 AC: 51 AN: 586

European-Finnish (FIN) AF: 0.0227 AC: 1 AN: 44

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 424

European-Non Finnish (NFE) AF: 0.0170 AC: 711 AN: 41816

Other (OTH) AF: 0.0335 AC: 191 AN: 5696

GnomAD4 genome AF: 0.0332 AC: 5050 AN: 152212 Hom.: 224 Cov.: 32 AF XY: 0.0369 AC XY: 2742 AN XY: 74402

African (AFR) AF: 0.00515 AC: 214 AN: 41526

American (AMR) AF: 0.111 AC: 1698 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3472

East Asian (EAS) AF: 0.171 AC: 884 AN: 5174

South Asian (SAS) AF: 0.0713 AC: 344 AN: 4822

European-Finnish (FIN) AF: 0.0475 AC: 503 AN: 10598

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0186 AC: 1267 AN: 68028

Other (OTH) AF: 0.0388 AC: 82 AN: 2112

Alfa AF: 0.0242 Hom.: 176

Bravo AF: 0.0387

Asia WGS AF: 0.126 AC: 436 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Microcephaly, normal intelligence and immunodeficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.89
DANN	Benign	0.26
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism (auto)

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: rs10464867; hg19: chr8-90945598;