8-26582018-C-T

Position:

• chr8-26582018-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.848

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPYSL2	ENST00000521913.7	c.404C>T	p.Ser135Leu	missense_variant	2/14	1	NM_001197293.3	ENSP00000427985
DPYSL2	ENST00000311151.9	c.89C>T	p.Ser30Leu	missense_variant	2/14	1		ENSP00000309539	P1
DPYSL2	ENST00000493789.6	c.305C>T	p.Ser102Leu	missense_variant	2/3	4		ENSP00000427954
DPYSL2	ENST00000523027.1	c.-20C>T		5_prime_UTR_variant	2/14	2		ENSP00000431117

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251290 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135834

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Nov 06, 2023

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
MutationTaster	Benign	1.0	D;D;D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1212338896; hg19: chr8-26439534;