SMARCD2

protein-coding

SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily d, member 2, the group of BAF complex|GBAF complex|PBAF complex

Gene summary

The protein encoded by this gene is a member of the SWI/SNF family of proteins, whose members display helicase and ATPase activities and which are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI and has sequence similarity to the yeast Swp73 protein. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001098426.2

Inheritance

ClinVar variants

P:32U:155B:119

Top phenotype

Specific granule defiency 2

gnomAD constraint

pLI —, LoF o/e 0.39

Max pathogenic AF

—

Genomic locus

chr17:63,832,081-63,843,065

External References & Databases

Ensembl (ENSG00000108604)

Transcript & Mutation Effects

hg38 • Region Span ~11.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

specific granule deficiency 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0044208

Submitter: Labcorp Genetics (formerly Invitae)

specific granule deficiency 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0044208

Submitter: PanelApp Australia

specific granule deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009506

Submitter: Orphanet

Clinical Genomic Database (CGD)

Specific granule defiency 2AR

Manifestation: Allergy/Immunology/Infectious; Craniofacial; Hematologic; Musculoskeletal; Neurologic

Intervention: Allergy/Immunology/Infectious

Rationale: Among other findings, individuals have been described with early-onset severe and recurrent infections, and antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial; HSCT has been described

Refs: 28369036

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SMARCD2 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 352

Inborn genetic diseasesTotal: 62

not specifiedTotal: 48

SMARCD2-related disorderTotal: 19

Specific granule deficiency 2Total: 13

Specific granule deficiency 1Total: 3

Autosomal recessive severe congenital neutropeniaTotal: 3

Primary ciliary dyskinesiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001098426.2. 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			4 clinvar	114 clinvar	1 clinvar	119
missense			144 clinvar	3 clinvar	1 clinvar	148
nonsense	9 clinvar	3 clinvar	1 clinvar			13
start loss			1 clinvar			1
frameshift	8 clinvar	4 clinvar	2 clinvar			14
splice donor/acceptor (+/-2bp)	3 clinvar	5 clinvar	3 clinvar			11
Total	20	12	155	117	2	306

Highest pathogenic variant AF is 0.000006570734

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001098426.2	RefSeq	NP_001091896.1	13	MANE Select
ENST00000448276.7	Ensembl	ENSP00000392617.2	13	MANE Select
NM_001330439.1	RefSeq	NP_001317368.1	12	Standard
NM_001330440.2	RefSeq	NP_001317369.1	13	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
smarcd2	Danio rerio	Structure: neutrophil Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

smarcd2

Danio rerio

Structure: neutrophil

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Thermogenesis - Homo sapiens (human)
Hepatocellular carcinoma - Homo sapiens (human)
Androgen Receptor Network in Prostate Cancer
Tumor suppressor activity of SMARCB1
Gene expression (Transcription)

Biological Process

nucleosome disassembly
chromatin remodeling
regulation of transcription by RNA polymerase II
ATP-dependent chromatin remodeling
positive regulation of nucleic acid-templated transcription

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
RNA polymerase II distal enhancer sequence-specific DNA binding
transcription coactivator activity
protein binding
nucleosomal DNA binding

Cellular Component

nuclear chromatin
nucleoplasm
SWI/SNF complex
protein-containing complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000448276
Coding exons: 13
Length: 10982
Individuals with no LoFs: 124677
Homozygous LoFs: 0
Heterozygous LoFs: 18
Defined: 124695
p: 0.0000722

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.22	184	291	0.633	0.0000178	3421
Missense (PolyPhen)		81	141.15	0.57387		1606
Synonymous	0.714	99	108	0.913	0.00000655	1089
Loss of Function	3.24	13	33.1	0.393	0.00000235	298

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000068	0.000064	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000056	0.000056	rare
Finnish	0.000048	0.000046	rare
European (Non-Finnish)	0.000089	0.000088	rare
South Asian	0.00010	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology). Component of SWI/SNF chromatin remodeling complexes that carry out key enzymatic activities, changing chromatin structure by altering DNA-histone contacts within a nucleosome in an ATP-dependent manner (PubMed:22952240, PubMed:26601204). Critical regulator of myeloid differentiation, controlling granulocytopoiesis and the expression of genes involved in neutrophil granule formation (PubMed:28369036). {ECO:0000269|PubMed:28369036, ECO:0000303|PubMed:22952240, ECO:0000303|PubMed:26601204}.;
Disease: DISEASE: Specific granule deficiency 2 (SGD2) [MIM:617475]: A form of specific granule deficiency, an autosomal recessive disorder characterized by recurrent pyogenic infections, defective neutrophil chemotaxis and bactericidal activity, and lack of neutrophil secondary granule proteins. SGD2 is due to defective neutrophil development. Bone marrow findings include hypercellularity, abnormal megakaryocytes, and features of progressive myelofibrosis with blasts. Some patients may have additional findings, including delayed development, mild dysmorphic features, and distal skeletal anomalies. {ECO:0000269|PubMed:28369036}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.113

Intolerance Scores

RVIS EVS: -0.21
RVIS percentile EVS: 38.58

Essentials

Essential (CRISPR): E
Essential (CRISPR2): N
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.973

Gene Damage Prediction

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