8-26643481-C-T

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

Scores

7
7
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.90
Variant links:
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]

Genome browser will be placed here

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
DPYSL2NM_001197293.3 linkuse as main transcriptc.1169C>T p.Thr390Met missense_variant 9/14 ENST00000521913.7 NP_001184222.1
DPYSL2NM_001386.6 linkuse as main transcriptc.854C>T p.Thr285Met missense_variant 9/14 NP_001377.1
DPYSL2NM_001244604.2 linkuse as main transcriptc.746C>T p.Thr249Met missense_variant 9/14 NP_001231533.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DPYSL2ENST00000521913.7 linkuse as main transcriptc.1169C>T p.Thr390Met missense_variant 9/141 NM_001197293.3 ENSP00000427985
DPYSL2ENST00000311151.9 linkuse as main transcriptc.854C>T p.Thr285Met missense_variant 9/141 ENSP00000309539 P1Q16555-1
DPYSL2ENST00000523027.1 linkuse as main transcriptc.746C>T p.Thr249Met missense_variant 9/142 ENSP00000431117 Q16555-2
DPYSL2ENST00000474808.1 linkuse as main transcriptn.525C>T non_coding_transcript_exon_variant 2/23

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152112
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000688
AC:
17
AN:
246992
Hom.:
0
AF XY:
0.0000825
AC XY:
11
AN XY:
133400
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.000147
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000335
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000537
Gnomad OTH exome
AF:
0.000333
GnomAD4 exome
AF:
0.0000329
AC:
48
AN:
1457766
Hom.:
0
Cov.:
30
AF XY:
0.0000276
AC XY:
20
AN XY:
725060
show subpopulations
Gnomad4 AFR exome
AF:
0.0000599
Gnomad4 AMR exome
AF:
0.000113
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000351
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000279
Gnomad4 OTH exome
AF:
0.0000664
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152112
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74302
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000378
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000824
AC:
10

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 submitterclinical testingAmbry GeneticsDec 21, 2022The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.65
.;D;.
Eigen
Uncertain
0.51
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.91
D;D;D
M_CAP
Pathogenic
0.31
D
MetaRNN
Pathogenic
0.86
D;D;D
MetaSVM
Uncertain
0.65
D
MutationAssessor
Benign
2.0
.;M;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Uncertain
-4.3
.;D;D
REVEL
Pathogenic
0.84
Sift
Benign
0.039
.;D;D
Sift4G
Benign
0.12
.;T;T
Polyphen
1.0
.;D;.
Vest4
0.85, 0.85
MVP
0.96
MPC
2.0
ClinPred
0.37
T
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.79
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199869101; hg19: chr8-26500997; API