rs202104448

Variant names:

• chr8-89984563-G-A
• rs202104448
• NM_002485.5:c.-2C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-89984563-G-A
• chr8-89984563-G-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_002485.5(NBN):​c.-2C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,613,110 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: NBN NM_002485.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:5
• Conservation: PhyloP100: 0.356
• Publications: 1 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

ENSG00000309953 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 8-89984563-G-A is Benign according to our data. Variant chr8-89984563-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 142094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89984563-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 142094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89984563-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 142094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89984563-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 142094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89984563-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 142094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89984563-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 142094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89984563-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 142094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89984563-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 142094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89984563-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 142094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89984563-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 142094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89984563-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 142094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89984563-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 142094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89984563-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 142094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89984563-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 142094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89984563-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 142094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89984563-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 142094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89984563-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 142094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89984563-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 142094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89984563-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 142094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89984563-G-A is described in CliVar as Benign/Likely_benign. Clinvar id is 142094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000383 (56/1460740) while in subpopulation EAS AF = 0.00134 (53/39682). AF 95% confidence interval is 0.00105. There are 0 homozygotes in GnomAdExome4. There are 19 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5	c.-2C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 16	ENST00000265433.8	NP_002476.2
NBN	NM_002485.5	c.-2C>T		5_prime_UTR_variant	Exon 1 of 16	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.-2C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 16	1	NM_002485.5	ENSP00000265433.4
NBN	ENST00000265433.8	c.-2C>T		5_prime_UTR_variant	Exon 1 of 16	1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152252 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000184 AC: 45 AN: 244888 AF XY: 0.000127

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00248

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000383 AC: 56 AN: 1460740 Hom.: 0 Cov.: 30 AF XY: 0.0000261 AC XY: 19 AN XY: 726738

African (AFR) AF: 0.0000299 AC: 1 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00134 AC: 53 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111750

Other (OTH) AF: 0.0000166 AC: 1 AN: 60294

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152370 Hom.: 0 Cov.: 33 AF XY: 0.0000939 AC XY: 7 AN XY: 74508

African (AFR) AF: 0.0000481 AC: 2 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000718

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:2

Jan 25, 2019

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Mar 24, 2025

Hereditary Cancer Laboratory, Hospital Universitario 12 de Octubre

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP6Supporting+BS1Strong -

Malignant tumor of breast Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NBN c.-2C>T variant was not identified in the literature nor was it identified in the Cosmic, LOVD 3.0, or Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs202104448) as “With Likely benign allele”, ClinVar (as likely benign by Ambry Genetics and GeneDx), and Clinvitae (2x). The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). This variant occurs within the Kozak promoter consensus sequence and a cytosine residue is normally located at this site. This is not enough information to determine the clinical significance with certainty. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Aplastic anemia;C0023449:Acute lymphoid leukemia;C0398791:Microcephaly, normal intelligence and immunodeficiency Benign:1

Jul 23, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Microcephaly, normal intelligence and immunodeficiency Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Aug 02, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	12
DANN	Benign	0.91
PhyloP100		0.36
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=295/5	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: rs202104448; hg19: chr8-90996791;