rs753950471
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Moderate
The NM_015214.3(DDHD2):c.1248+2T>C variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000712 in 1,404,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).
Frequency
Consequence
NM_015214.3 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DDHD2 | NM_015214.3 | c.1248+2T>C | splice_donor_variant | ENST00000397166.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DDHD2 | ENST00000397166.7 | c.1248+2T>C | splice_donor_variant | 2 | NM_015214.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 exomes AF: 0.00000991 AC: 2AN: 201732Hom.: 0 AF XY: 0.0000181 AC XY: 2AN XY: 110762
GnomAD4 exome AF: 0.00000712 AC: 10AN: 1404748Hom.: 0 Cov.: 27 AF XY: 0.00000858 AC XY: 6AN XY: 699160
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Hereditary spastic paraplegia 54 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 08, 2017 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in DDHD2 are known to be pathogenic (PMID: 23176823, 23486545). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with DDHD2-related disease. This variant is present in population databases (rs753950471, ExAC 0.007%). This sequence change affects a donor splice site in intron 10 of the DDHD2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at