rs373856119
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_015214.3(DDHD2):c.1546C>T(p.Arg516Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
DDHD2
NM_015214.3 stop_gained
NM_015214.3 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 3.28
Genes affected
DDHD2 (HGNC:29106): (DDHD domain containing 2) This gene encodes a phospholipase enzyme containing sterile-alpha-motif (SAM), WWE, and DDHD domains. This protein participates in membrane trafficking between the endoplastic reticulum and the Golgi body. Mutations in this gene can cause autosomal recessive spastic paraplegia 54. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 8-38252216-C-T is Pathogenic according to our data. Variant chr8-38252216-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 39680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| DDHD2 | NM_015214.3 | c.1546C>T | p.Arg516Ter | stop_gained | 13/18 | ENST00000397166.7 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| DDHD2 | ENST00000397166.7 | c.1546C>T | p.Arg516Ter | stop_gained | 13/18 | 2 | NM_015214.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152104Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251296Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135818
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GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461830Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727208
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152104Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74296
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 54 Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 17, 2022 | This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 23176823). It has also been observed to segregate with disease in related individuals. This sequence change creates a premature translational stop signal (p.Arg516*) in the DDHD2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DDHD2 are known to be pathogenic (PMID: 23176823, 23486545). This variant is present in population databases (rs373856119, gnomAD 0.01%). ClinVar contains an entry for this variant (Variation ID: 39680). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | curation | Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University | Dec 30, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. It has been reported at least twice as pathogenic without evidence for the classification (PMID: 23176823). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 07, 2012 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at