rs375064450
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_015214.3(DDHD2):c.1744A>T(p.Met582Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000088 in 1,614,048 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000085 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000088 ( 0 hom. )
Consequence
DDHD2
NM_015214.3 missense
NM_015214.3 missense
Scores
2
1
15
Clinical Significance
Conservation
PhyloP100: 6.22
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 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.30945575).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DDHD2 | NM_015214.3 | c.1744A>T | p.Met582Leu | missense_variant | 15/18 | ENST00000397166.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DDHD2 | ENST00000397166.7 | c.1744A>T | p.Met582Leu | missense_variant | 15/18 | 2 | NM_015214.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152206Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.0000637 AC: 16AN: 251334Hom.: 0 AF XY: 0.0000515 AC XY: 7AN XY: 135846
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GnomAD4 exome AF: 0.0000882 AC: 129AN: 1461842Hom.: 0 Cov.: 31 AF XY: 0.0000880 AC XY: 64AN XY: 727230
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GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152206Hom.: 1 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74370
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Sep 13, 2016 | - - |
Hereditary spastic paraplegia 54 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 18, 2022 | 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 sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 434908). This variant has not been reported in the literature in individuals affected with DDHD2-related conditions. This variant is present in population databases (rs375064450, gnomAD 0.01%). This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 582 of the DDHD2 protein (p.Met582Leu). - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 27, 2022 | The c.1744A>T (p.M582L) alteration is located in exon 15 (coding exon 14) of the DDHD2 gene. This alteration results from a A to T substitution at nucleotide position 1744, causing the methionine (M) at amino acid position 582 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Benign
DEOGEN2
Benign
T;T;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
T
PROVEAN
Benign
N;N;N;N
REVEL
Benign
Sift
Benign
T;T;T;T
Sift4G
Benign
T;T;T;T
Polyphen
P;P;.;.
Vest4
MutPred
Loss of helix (P = 0.028);Loss of helix (P = 0.028);.;.;
MVP
MPC
ClinPred
T
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