GeneBe

MAD2L2

protein-coding

mitotic arrest deficient 2 like 2, the group of DNA polymerases|FA complementation groups

Gene summary

The protein encoded by this gene is a component of the mitotic spindle assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at the metaphase plate. The encoded protein, which is similar to MAD2L1, is capable of interacting with ADAM9, ADAM15, REV1, and REV3 proteins. [provided by RefSeq, Jul 2008]

MANE transcript

NM_006341.4

Inheritance

AR

ClinVar variants

P:1U:68B:49

Top phenotype

Fanconi anemia, complementation group V

gnomAD constraint

pLI —, LoF o/e 0.31

Max pathogenic AF

—

Genomic locus

chr1:11,657,230-11,691,811

External References & Databases

Ensembl (ENSG00000116670)NCBI Gene (10459)OMIM (604094)HGNC:6764GenCCUniProt (Q9UI95)AlphaFoldClinVar (MAD2L2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~34.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Fanconi anemia complementation group VLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014985

Submitter: PanelApp Australia

Fanconi anemia complementation group VLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0014985

Submitter: Labcorp Genetics (formerly Invitae)

Fanconi anemiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019391

Submitter: Orphanet

Fanconi anemia complementation group VLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014985

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Fanconi anemia, complementation group VAR

Manifestation: Cardiovascular; Craniofacial; Hematologic; Neurologic; Oncologic

Intervention: Cardiovascular; Hematologic; Oncologic

Rationale: Specific treatments can help manifestations (eg, oral androgens for blood counts; G-CSF for neutrophil count); Individuals may be at risk for certain types of cancer, and awareness may allow early diagnosis and management; Surveillance for complications such as bone marrow failure is recommended; Fanconi anemia can involve congenital cardiac (and other) anomalies, and awareness may allow early management

Refs: 27500492Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MAD2L2 variants in ClinVar

7 Conditions Cataloged
not providedTotal: 172
not specifiedTotal: 31
MAD2L2-related disorderTotal: 13
Abnormal sperm morphologyTotal: 1
Fanconi anemia complementation group VTotal: 1
Reduced sperm motilityTotal: 1
OligospermiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006341.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
4
clinvar
47
clinvar
1
clinvar
 52
missense
1
clinvar
49
clinvar
1
clinvar
 51
nonsense
3
clinvar
 3
start loss
1
clinvar
 1
frameshift
5
clinvar
 5
splice donor/acceptor (+/-2bp)
6
clinvar
 6
Total1068481118
Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 103 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_006341.4RefSeqNP_006332.38MANE Select
ENST00000376692.9EnsemblENSP00000365882.48MANE Select
NM_001127325.2RefSeqNP_001120797.18Standard
ENST00000235310.7EnsemblENSP00000235310.28Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Cell cycle - Homo sapiens (human)
  • Oocyte meiosis - Homo sapiens (human)
  • Bacterial invasion of epithelial cells - Homo sapiens (human)
  • Shigellosis - Homo sapiens (human)
  • Progesterone-mediated oocyte maturation - Homo sapiens (human)

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • regulation of cell growth
  • double-strand break repair
  • actin filament organization
  • mitotic spindle assembly checkpoint

Molecular Function

  • RNA polymerase II activating transcription factor binding
  • protein binding
  • JUN kinase binding

Cellular Component

  • nucleus
  • nucleoplasm
  • anaphase-promoting complex
  • chromosome
  • nucleolus

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000235310
Coding exons
8
Length
17171
Individuals with no LoFs
125722
Homozygous LoFs
0
Heterozygous LoFs
14
Defined
125736
p
0.0000557
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.57811320.6150.000008041388
Missense (PolyPhen)1733.6750.50482368
Synonymous1.014857.80.8300.00000386409
Loss of Function2.27412.80.3135.52e-7142

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American00.0absent
Ashkenazi Jewish0.000100.000099rare
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.000110.00011rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Adapter protein able to interact with different proteins and involved in different biological processes (PubMed:11459825, PubMed:11459826, PubMed:17719540, PubMed:17296730, PubMed:19443654, PubMed:29656893). Mediates the interaction between the error-prone DNA polymerase zeta catalytic subunit REV3L and the inserter polymerase REV1, thereby mediating the second polymerase switching in translesion DNA synthesis (PubMed:20164194). Translesion DNA synthesis releases the replication blockade of replicative polymerases, stalled in presence of DNA lesions (PubMed:20164194). Component of the shieldin complex, which plays an important role in repair of DNA double-stranded breaks (DSBs) (PubMed:29656893). During G1 and S phase of the cell cycle, the complex functions downstream of TP53BP1 to promote non-homologous end joining (NHEJ) and suppress DNA end resection (PubMed:29656893). Mediates various NHEJ- dependent processes including immunoglobulin class-switch recombination, and fusion of unprotected telomeres (PubMed:29656893). May also regulate another aspect of cellular response to DNA damage through regulation of the JNK-mediated phosphorylation and activation of the transcriptional activator ELK1 (PubMed:17296730). Inhibits the FZR1- and probably CDC20- mediated activation of the anaphase promoting complex APC thereby regulating progression through the cell cycle (PubMed:11459825, PubMed:17719540). Regulates TCF7L2-mediated gene transcription and may play a role in epithelial-mesenchymal transdifferentiation (PubMed:19443654). {ECO:0000269|PubMed:11459825, ECO:0000269|PubMed:11459826, ECO:0000269|PubMed:17296730, ECO:0000269|PubMed:17719540, ECO:0000269|PubMed:19443654, ECO:0000269|PubMed:20164194, ECO:0000269|PubMed:29656893}.;

Recessive Scores

pRec
0.134

Intolerance Scores

LoFtool
0.395
RVIS EVS
0.06
RVIS percentile EVS
58.26

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
E
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.991

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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