MACROH2A2

protein-coding

macroH2A.2 histone, the group of H2A histones|Macro domain containing

Gene summary

Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Nucleosomes consist of approximately 146 bp of DNA wrapped around a histone octamer composed of pairs of each of the four core histones (H2A, H2B, H3, and H4). The chromatin fiber is further compacted through the interaction of a linker histone, H1, with the DNA between the nucleosomes to form higher order chromatin structures. This gene encodes a replication-independent histone that is a member of the histone H2A family. It replaces conventional H2A histones in a subset of nucleosomes where it represses transcription and may participate in stable X chromosome inactivation. [provided by RefSeq, Oct 2015]

Previous symbols:

H2AFY2

MANE transcript

NM_018649.3

Inheritance

—

ClinVar variants

U:42B:2

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr10:70,052,544-70,112,282

External References & Databases

Ensembl (ENSG00000099284)

Transcript & Mutation Effects

hg38 • Region Span ~59.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MACROH2A2 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 36

not providedTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018649.3. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar		2 clinvar	5
missense			39 clinvar			39
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	42	0	2	44

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 30 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018649.3	RefSeq	NP_061119.1	8	MANE Select
ENST00000373255.9	Ensembl	ENSP00000362352.3	8	MANE Select
ENST00000455786.1	Ensembl	ENSP00000404584.1	6	Standard
ENST00000676608.1	Ensembl	ENSP00000503921.1	1	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
h2afy2	Danio rerio	Structure: midbrain hindbrain boundary neural tube Quality: cleft abnormal

Gene / Model

Organism

Observed Phenotype

h2afy2

Danio rerio

Structure: midbrain hindbrain boundary neural tube

Quality: cleft

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Systemic lupus erythematosus - Homo sapiens (human)
Necroptosis - Homo sapiens (human)
Alcoholism - Homo sapiens (human)
Preimplantation Embryo

Biological Process

negative regulation of transcription by RNA polymerase II
chromatin organization
nucleosome assembly
brain development
dosage compensation

Molecular Function

RNA polymerase II regulatory region sequence-specific DNA binding
DNA binding
chromatin DNA binding
transcription regulatory region DNA binding
protein heterodimerization activity

Cellular Component

nuclear chromosome, telomeric region
nucleosome
nuclear chromatin
Barr body
nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000373255
Coding exons: 8
Length: 59485
Individuals with no LoFs: 125743
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125747
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.92	110	236	0.466	0.0000151	2408
Missense (PolyPhen)		25	101.36	0.24664		1044
Synonymous	0.557	100	107	0.932	0.00000809	747
Loss of Function	3.46	1	15.9	0.0629	7.53e-7	212

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Variant histone H2A which replaces conventional H2A in a subset of nucleosomes where it represses transcription. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post- translational modifications of histones, also called histone code, and nucleosome remodeling. May be involved in stable X chromosome inactivation. {ECO:0000269|PubMed:15621527}.;

Recessive Scores

pRec: 0.183

Intolerance Scores

RVIS EVS: -0.54
RVIS percentile EVS: 20.54

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.921

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium