rs201156715
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_015214.3(DDHD2):āc.1090C>Gā(p.Gln364Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000945 in 1,609,024 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 Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000053 ( 0 hom., cov: 33)
Exomes š: 0.000099 ( 0 hom. )
Consequence
DDHD2
NM_015214.3 missense
NM_015214.3 missense
Scores
5
8
5
Clinical Significance
Conservation
PhyloP100: 6.80
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 Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.8
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DDHD2 | NM_015214.3 | c.1090C>G | p.Gln364Glu | missense_variant | 9/18 | ENST00000397166.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DDHD2 | ENST00000397166.7 | c.1090C>G | p.Gln364Glu | missense_variant | 9/18 | 2 | NM_015214.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152146Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000481 AC: 12AN: 249664Hom.: 0 AF XY: 0.0000593 AC XY: 8AN XY: 134826
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GnomAD4 exome AF: 0.0000988 AC: 144AN: 1456878Hom.: 0 Cov.: 29 AF XY: 0.000116 AC XY: 84AN XY: 724960
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GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152146Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74316
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 54 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 06, 2022 | This variant is present in population databases (rs201156715, gnomAD 0.009%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 473070). This variant has not been reported in the literature in individuals affected with DDHD2-related conditions. This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 364 of the DDHD2 protein (p.Gln364Glu). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 12, 2018 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 24, 2021 | Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533, 23176823) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
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