8-26643481-C-T
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP2PP3_ModerateBS2
The NM_001197293.3(DPYSL2):c.1169C>T(p.Thr390Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,609,878 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 (★).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000033 ( 0 hom. )
Consequence
DPYSL2
NM_001197293.3 missense
NM_001197293.3 missense
Scores
7
7
5
Clinical Significance
Conservation
PhyloP100: 7.90
Genes affected
DPYSL2 (HGNC:3014): (dihydropyrimidinase like 2) This gene encodes a member of the collapsin response mediator protein family. Collapsin response mediator proteins form homo- and hetero-tetramers and facilitate neuron guidance, growth and polarity. The encoded protein promotes microtubule assembly and is required for Sema3A-mediated growth cone collapse, and also plays a role in synaptic signaling through interactions with calcium channels. This gene has been implicated in multiple neurological disorders, and hyperphosphorylation of the encoded protein may play a key role in the development of Alzheimer's disease. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Sep 2011]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DPYSL2. . Gene score misZ 3.8756 (greater than the threshold 3.09). Trascript score misZ 3.9251 (greater than threshold 3.09). GenCC has associacion of gene with schizophrenia.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.858
BS2
High AC in GnomAd4 at 5 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DPYSL2 | NM_001197293.3 | c.1169C>T | p.Thr390Met | missense_variant | 9/14 | ENST00000521913.7 | NP_001184222.1 | |
DPYSL2 | NM_001386.6 | c.854C>T | p.Thr285Met | missense_variant | 9/14 | NP_001377.1 | ||
DPYSL2 | NM_001244604.2 | c.746C>T | p.Thr249Met | missense_variant | 9/14 | NP_001231533.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DPYSL2 | ENST00000521913.7 | c.1169C>T | p.Thr390Met | missense_variant | 9/14 | 1 | NM_001197293.3 | ENSP00000427985 | ||
DPYSL2 | ENST00000311151.9 | c.854C>T | p.Thr285Met | missense_variant | 9/14 | 1 | ENSP00000309539 | P1 | ||
DPYSL2 | ENST00000523027.1 | c.746C>T | p.Thr249Met | missense_variant | 9/14 | 2 | ENSP00000431117 | |||
DPYSL2 | ENST00000474808.1 | n.525C>T | non_coding_transcript_exon_variant | 2/2 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152112Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000688 AC: 17AN: 246992Hom.: 0 AF XY: 0.0000825 AC XY: 11AN XY: 133400
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GnomAD4 exome AF: 0.0000329 AC: 48AN: 1457766Hom.: 0 Cov.: 30 AF XY: 0.0000276 AC XY: 20AN XY: 725060
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GnomAD4 genome AF: 0.0000329 AC: 5AN: 152112Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74302
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 21, 2022 | The c.1169C>T (p.T390M) alteration is located in exon 9 (coding exon 9) of the DPYSL2 gene. This alteration results from a C to T substitution at nucleotide position 1169, causing the threonine (T) at amino acid position 390 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;M;.
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
.;D;D
REVEL
Pathogenic
Sift
Benign
.;D;D
Sift4G
Benign
.;T;T
Polyphen
1.0
.;D;.
Vest4
0.85, 0.85
MVP
MPC
2.0
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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