NM_002485.5(NBN):c.2231T>G (p.Phe744Cys) AND Microcephaly, normal intelligence and immunodeficiency

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 19, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003618496.2

Allele description [Variation Report for NM_002485.5(NBN):c.2231T>G (p.Phe744Cys)]

NM_002485.5(NBN):c.2231T>G (p.Phe744Cys)

Gene:

NBN:nibrin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8q21.3

Genomic location:

Preferred name:

NM_002485.5(NBN):c.2231T>G (p.Phe744Cys)

HGVS:

NC_000008.11:g.89937029A>C
NG_008860.1:g.52643T>G
NM_001024688.3:c.1985T>G
NM_002485.5:c.2231T>GMANE SELECT
NP_001019859.1:p.Phe662Cys
NP_002476.2:p.Phe744Cys
NP_002476.2:p.Phe744Cys
LRG_158t1:c.2231T>G
LRG_158:g.52643T>G
LRG_158p1:p.Phe744Cys
NC_000008.10:g.90949257A>C
NM_002485.4:c.2231T>G

Protein change:

F662C

Molecular consequence:

NM_001024688.3:c.1985T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_002485.5:c.2231T>G - 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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Homo sapiens family with sequence similarity 185 member A (FAM185A), transcript ...
Homo sapiens family with sequence similarity 185 member A (FAM185A), transcript variant 4, mRNA
gi|1890267663|ref|NM_001350987.2|

Nucleotide
SRX7866609 (1)
SRA
NADH dehydrogenase subunit 2 (mitochondrion) [Tylomelania marwotoae]
NADH dehydrogenase subunit 2 (mitochondrion) [Tylomelania marwotoae]
gi|2704297859|gb|WXX01563.1|

Protein
NADH dehydrogenase subunit 4L (mitochondrion) [Tylomelania abendanoni]
NADH dehydrogenase subunit 4L (mitochondrion) [Tylomelania abendanoni]
gi|2704298279|gb|WXX01773.1|

Protein
Active FOXO1 is a Key Determinant of Isoform-Specific Progesterone Receptor Tran...
Active FOXO1 is a Key Determinant of Isoform-Specific Progesterone Receptor Transactivation and Senescence Programming
Active FOXO1 is a Key Determinant of Isoform-Specific Progesterone Receptor Transactivation and Senescence Programming

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004485381	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 19, 2023)	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

SCV004485381

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 19, 2023)

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	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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004485381.1

#	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 phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 744 of the NBN protein (p.Phe744Cys). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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

Last Updated: Sep 29, 2024

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