RAI2

protein-coding

retinoic acid induced 2

Gene summary

Retinoic acid plays a critical role in development, cellular growth, and differentiation. The specific function of this retinoic acid-induced gene has not yet been determined but it may play a role in development. The chromosomal location of this gene designates it to be a candidate for diseases such as Nance-Horan syndrome, sensorineural deafness, non-specific X-linked cognitive disability, oral-facial-digital syndrome, and Fried syndrome. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2010]

MANE transcript

NM_021785.6

Inheritance

ClinVar variants

U:113B:10

Top phenotype

Dextrocardia

gnomAD constraint

pLI —, LoF o/e 0.14

Max pathogenic AF

—

Genomic locus

chrX:17,800,049-17,861,337

External References & Databases

Ensembl (ENSG00000131831)

Transcript & Mutation Effects

hg38 • Region Span ~61.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital heart diseaseNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

RAI2 was first reported in relation to autosomal dominant congenital heart disease in 2019 (Li et al., PMID: 30622330). One variant (a missense) that has been reported in one proband in one publication (PMID: 30622330) is included in this curation. However, this variant was not scored as it is too frequent and present in the hemizygous state in population databases. No scorable experimental evidence was found. The only experimental evidence evaluated was expression analysis in human fetal tissue. However, this was not counted as there was no fetal heart expression and there is no scorable genetic evidence. In summary, the evidence supporting the relationship between RAI2 and autosomal dominant congenital heart disease has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role RAI2 plays in this disease. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 4/30/2024 (SOP Version 10).

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RAI2 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 78

not providedTotal: 11

DextrocardiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_021785.6. 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			13 clinvar	4 clinvar	4 clinvar	21
missense			95 clinvar	1 clinvar	1 clinvar	97
nonsense			1 clinvar			1
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	0	113	5	5	123

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 50 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_021785.6	RefSeq	NP_068557.4	1	MANE Select
ENST00000451717.6	Ensembl	ENSP00000401323.1	1	MANE Select
NM_001172732.2	RefSeq	NP_001166203.2	2	Standard
NM_001172739.2	RefSeq	NP_001166210.2	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

embryo development ending in birth or egg hatching

Molecular Function

molecular_function
protein binding

Cellular Component

cellular_component

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000545871
Coding exons: 1
Length: 61289
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 3
Defined: 125740
p: 0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0606	217	215	1.01	0.0000165	3492
Missense (PolyPhen)		29	38.063	0.76189		625
Synonymous	-0.471	102	96.1	1.06	0.00000818	1104
Loss of Function	2.15	1	7.23	0.138	4.57e-7	136

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000076	0.000062	rare
Latino/Admixed American	0.000036	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000012	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Recessive Scores

pRec: 0.0996

Intolerance Scores

LoFtool: 0.243
RVIS EVS: -0.42
RVIS percentile EVS: 25.56

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.590

Gene Damage Prediction

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