GeneBe

NM_001197293.3:c.404C>A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_001197293.3(DPYSL2):​c.404C>A​(p.Ser135*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DPYSL2
NM_001197293.3 stop_gained

Scores

5
1
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.90

Publications

0 publications found
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]
DPYSL2 Gene-Disease associations (from GenCC):
  • schizophrenia
    Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DPYSL2NM_001197293.3 linkc.404C>A p.Ser135* stop_gained Exon 2 of 14 ENST00000521913.7 NP_001184222.1 Q16555Q59GB4A0A1C7CYX9
DPYSL2NM_001386.6 linkc.89C>A p.Ser30* stop_gained Exon 2 of 14 NP_001377.1 Q16555-1
DPYSL2NM_001244604.2 linkc.-20C>A 5_prime_UTR_variant Exon 2 of 14 NP_001231533.1 Q16555-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DPYSL2ENST00000521913.7 linkc.404C>A p.Ser135* stop_gained Exon 2 of 14 1 NM_001197293.3 ENSP00000427985.2 A0A1C7CYX9
DPYSL2ENST00000311151.9 linkc.89C>A p.Ser30* stop_gained Exon 2 of 14 1 ENSP00000309539.5 Q16555-1
DPYSL2ENST00000493789.6 linkc.305C>A p.Ser102* stop_gained Exon 2 of 3 4 ENSP00000427954.1 E5RFU4
DPYSL2ENST00000523027.1 linkc.-20C>A 5_prime_UTR_variant Exon 2 of 14 2 ENSP00000431117.1 Q16555-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461620
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
727098
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
33476
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39686
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86224
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53260
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111962
Other (OTH)
AF:
0.00
AC:
0
AN:
60386
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.62
D
BayesDel_noAF
Pathogenic
0.66
CADD
Pathogenic
44
DANN
Uncertain
1.0
Eigen
Pathogenic
0.94
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
0.99
D
PhyloP100
7.9
Vest4
0.87
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Mutation Taster
=0/200
disease causing (fs/PTC)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs1212338896; hg19: chr8-26439534; API