chr8-26582018-C-T

Variant names:

• chr8-26582018-C-T
• rs1212338896
• NM_001197293.3:c.404C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001197293.3(DPYSL2):​c.404C>T​(p.Ser135Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,624 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: DPYSL2 NM_001197293.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.90
• Publications: 1 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPYSL2	NM_001197293.3	c.404C>T	p.Ser135Leu	missense_variant	Exon 2 of 14	ENST00000521913.7	NP_001184222.1
DPYSL2	NM_001244604.2	c.-20C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 14		NP_001231533.1
DPYSL2	NM_001386.6	c.89C>T	p.Ser30Leu	missense_variant	Exon 2 of 14		NP_001377.1
DPYSL2	NM_001244604.2	c.-20C>T		5_prime_UTR_variant	Exon 2 of 14		NP_001231533.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPYSL2	ENST00000521913.7	c.404C>T	p.Ser135Leu	missense_variant	Exon 2 of 14	1	NM_001197293.3	ENSP00000427985.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251290 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461624 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727100

⚠️ 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: 0.00 AC: 0 AN: 86228

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: 0.00000270 AC: 3 AN: 1111962

Other (OTH) AF: 0.0000166 AC: 1 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.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 06, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DPYSL2 c.404C>T (p.Ser135Leu) variant, to our knowledge, has not been reported in the medical literature. This variant is only observed on 1/251,290 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant occurs in a beta sheet and changes a polar serine to a nonpolar leucine and computational predictors indicate that the variant is damaging, evidence that correlates with impact to DPYSL2 function. Due to limited information, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.084	.;T;D
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	1.7	.;.;L
PhyloP100		7.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.9	.;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0020	.;D;D
Sift4G	Uncertain	0.042	.;D;T
Polyphen		1.0	.;.;D
Vest4		0.80
MutPred		0.50		.;.;Loss of sheet (P = 0.0817);
MVP		0.95
MPC		1.7
ClinPred		0.98	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.89
Mutation Taster		=16/84	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1212338896; hg19: chr8-26439534;