DDHD2

DDHD domain containing 2, the group of Sterile alpha motif domain containing

Basic information

Region (hg38): 8:38225218-38275558

Previous symbols: [ "SAMWD1" ]

Links

ENSG00000085788 ∙ NCBI:23259 ∙ OMIM:615003 ∙ HGNC:29106 ∙ Uniprot:O94830 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hereditary spastic paraplegia 54 (Definitive), mode of inheritance: AR
• hereditary spastic paraplegia 54 (Strong), mode of inheritance: AR
• hereditary spastic paraplegia 54 (Supportive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Spastic paraplegia 54	AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Neurologic	16636240; 23176823; 24482476

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the DDHD2 gene.

• Hereditary_spastic_paraplegia_54 (235 variants)
• Inborn_genetic_diseases (75 variants)
• not_provided (65 variants)
• not_specified (32 variants)
• Hereditary_spastic_paraplegia (24 variants)
• DDHD2-related_disorder (5 variants)
• Senior-Loken_syndrome_6 (2 variants)
• Obesity (1 variants)
• Global_developmental_delay (1 variants)
• Generalized_epilepsy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the DDHD2 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000015214.3. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			4	64		68
missense	1	4	140	10	1	156
nonsense	9	9				18
start loss						0
frameshift	7	6	1			14
splice donor/acceptor (+/-2bp)		4	2			6
Total	17	23	147	74	1

Highest pathogenic variant AF is 0.000132581

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
DDHD2	protein_coding	protein_coding	ENST00000397166	16	50341

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.43e-10	0.997	125680	1	67	125748	0.000270

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.07	317	375	0.845	0.0000186	4677
Missense in Polyphen		107	151.62	0.7057		1871
Synonymous	0.419	128	134	0.954	0.00000676	1326
Loss of Function	2.76	23	42.4	0.543	0.00000236	490

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000970	0.000909
Ashkenazi Jewish	0.000226	0.000198
East Asian	0.000273	0.000272
Finnish	0.0000926	0.0000924
European (Non-Finnish)	0.000215	0.000211
Middle Eastern	0.000273	0.000272
South Asian	0.000478	0.000392
Other	0.000537	0.000489

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Phospholipase that hydrolyzes preferentially phosphatidic acid, including 1,2-dioleoyl-sn-phosphatidic acid, and phosphatidylethanolamine. Specifically binds to phosphatidylinositol 3-phosphate (PI(3)P), phosphatidylinositol 4- phosphate (PI(4)P), phosphatidylinositol 5-phosphate (PI(5)P) and possibly phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). May be involved in the maintenance of the endoplasmic reticulum and/or Golgi structures. May regulate the transport between Golgi apparatus and plasma membrane. {ECO:0000269|PubMed:11788596, ECO:0000269|PubMed:20932832, ECO:0000269|PubMed:22922100}.
• Disease: DISEASE: Spastic paraplegia 54, autosomal recessive (SPG54) [MIM:615033]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. Complicated forms are recognized by additional variable features including spastic quadriparesis, seizures, dementia, amyotrophy, extrapyramidal disturbance, cerebral or cerebellar atrophy, optic atrophy, and peripheral neuropathy, as well as by extra neurological manifestations. SPG54 patients have delayed psychomotor development, intellectual disability, and early-onset spasticity of the lower limbs. Brain MRI shows a thin corpus callosum and periventricular white matter lesions. {ECO:0000269|PubMed:23176823, ECO:0000269|PubMed:24482476}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Metabolism of lipids;Metabolism;Glycerophospholipid biosynthesis;Phospholipid metabolism;Synthesis of PA (Consensus)

Recessive Scores

• pRec: 0.0892

Intolerance Scores

• loftool: 0.977
• rvis_EVS: -0.15
• rvis_percentile_EVS: 42.23

Haploinsufficiency Scores

• pHI: 0.108
• hipred: N
• hipred_score: 0.443
• ghis: 0.551

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.307

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ddhd2
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); homeostasis/metabolism phenotype

Gene ontology

• Biological process: endoplasmic reticulum to Golgi vesicle-mediated transport;locomotory behavior;visual learning;triglyceride catabolic process;lipid droplet organization;macromolecule metabolic process;positive regulation of mitochondrial fission
• Cellular component: endoplasmic reticulum-Golgi intermediate compartment;Golgi apparatus;microtubule organizing center;cytosol;membrane;COPII-coated ER to Golgi transport vesicle
• Molecular function: phospholipase activity;triglyceride lipase activity;metal ion binding