SIM2

protein-coding

SIM bHLH transcription factor 2, the group of Basic helix-loop-helix proteins|PAS domain containing

Gene summary

This gene represents a homolog of the Drosophila single-minded (sim) gene, which encodes a transcription factor that is a master regulator of neurogenesis. The encoded protein is ubiquitinated by RING-IBR-RING-type E3 ubiquitin ligases, including the parkin RBR E3 ubiquitin protein ligase. This gene maps within the so-called Down syndrome chromosomal region, and is thus thought to contribute to some specific Down syndrome phenotypes. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Sep 2014]

Previous symbols:

MANE transcript

NM_005069.6

Inheritance

—

ClinVar variants

P:1U:112B:11

Top phenotype

Neurodevelopmental with craniofacial anomalies disorder

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr21:36,699,115-36,749,917

External References & Databases

Ensembl (ENSG00000159263)

Transcript & Mutation Effects

hg38 • Region Span ~50.8 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 SIM2 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 112

not providedTotal: 8

Neurodevelopmental with craniofacial anomalies disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005069.6. 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				6 clinvar	3 clinvar	9
missense		1 clinvar	110 clinvar	2 clinvar		113
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	1	112	8	3	124

Highest pathogenic variant AF is 0.000034079952

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005069.6	RefSeq	NP_005060.1	11	MANE Select
ENST00000290399.11	Ensembl	ENSP00000290399.6	11	MANE Select
NM_009586.5	RefSeq	NP_033664.2	10	Standard
ENST00000431229.1	Ensembl	ENSP00000392003.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

negative regulation of transcription by RNA polymerase II
regulation of transcription by RNA polymerase II
nervous system development
embryonic pattern specification
cell differentiation

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
DNA-binding transcription factor activity
protein heterodimerization activity

Cellular Component

nucleus
nucleoplasm
nuclear body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000290399
Coding exons: 11
Length: 50786
Individuals with no LoFs: 125730
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125747
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.962	268	316	0.848	0.0000182	4237
Missense (PolyPhen)		85	116.03	0.73257		1340
Synonymous	-0.396	152	146	1.04	0.00000984	1373
Loss of Function	3.75	7	28.7	0.244	0.00000147	334

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000060	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000081	0.000079	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transcription factor that may be a master gene of CNS development in cooperation with Arnt. It may have pleiotropic effects in the tissues expressed during development.;

Recessive Scores

pRec: 0.247

Intolerance Scores

LoFtool: 0.632
RVIS EVS: -0.2
RVIS percentile EVS: 39.17

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.987

Gene Damage Prediction

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