NM_002485.5(NBN):c.2191A>T (p.Asn731Tyr) AND Microcephaly, normal intelligence and immunodeficiency

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 11, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001049269.9

Allele description [Variation Report for NM_002485.5(NBN):c.2191A>T (p.Asn731Tyr)]

NM_002485.5(NBN):c.2191A>T (p.Asn731Tyr)

Gene:

NBN:nibrin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8q21.3

Genomic location:

Preferred name:

NM_002485.5(NBN):c.2191A>T (p.Asn731Tyr)

Other names:

p.N731Y:AAT>TAT

HGVS:

NC_000008.11:g.89937069T>A
NG_008860.1:g.52603A>T
NM_001024688.3:c.1945A>T
NM_002485.5:c.2191A>TMANE SELECT
NP_001019859.1:p.Asn649Tyr
NP_002476.2:p.Asn731Tyr
NP_002476.2:p.Asn731Tyr
LRG_158t1:c.2191A>T
LRG_158:g.52603A>T
LRG_158p1:p.Asn731Tyr
NC_000008.10:g.90949297T>A
NM_002485.4:c.2191A>T

Protein change:

N649Y

Links:

dbSNP: rs369649307

NCBI 1000 Genomes Browser:

rs369649307

Molecular consequence:

NM_001024688.3:c.1945A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002485.5:c.2191A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Microcephaly, normal intelligence and immunodeficiency (NBS)
Synonyms:: IMMUNODEFICIENCY, MICROCEPHALY, AND CHROMOSOMAL INSTABILITY; SEEMANOVA SYNDROME II; Nijmegen breakage syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009623; MedGen: C0398791; Orphanet: 647; OMIM: 251260

Recent activity

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Mus musculus synaptosomal-associated protein 23 (Snap23), mRNA
Mus musculus synaptosomal-associated protein 23 (Snap23), mRNA
gi|6678048|ref|NM_009222.1|

Nucleotide
hypothetical protein CCH79_00005121, partial [Gambusia affinis]
hypothetical protein CCH79_00005121, partial [Gambusia affinis]
gi|1387731998|gb|PWA25162.1||gnl|WG Q|CCH79_00005121-RA

Protein
aspartate--tRNA ligase [Trichonephila inaurata madagascariensis]
aspartate--tRNA ligase [Trichonephila inaurata madagascariensis]
gi|2071164976|dbj|GFY43535.1||gnl|W AV|GFY43535

Protein
hypothetical protein GOS_5098719, partial [marine metagenome]
hypothetical protein GOS_5098719, partial [marine metagenome]
gi|140050222|gb|ECJ24321.1||gnl|WGS |JCVI_PEP_1096691963771

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001213313	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 11, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002046038	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001213313

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 11, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002046038

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Nov 7, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001213313.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 731 of the NBN protein (p.Asn731Tyr). This variant is present in population databases (rs369649307, gnomAD 0.0009%). 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: 127866). 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: "Deleterious"; 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002046038.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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