8-26643481-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP2 PP3_Moderate BS2

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 (★). Synonymous variant affecting the same amino acid position (i.e. T390T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (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 Likely_benign. Variant got -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DPYSL2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.858
• BS2: High AC in GnomAd at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DPYSL2	NM_001197293.3	c.1169C>T	p.Thr390Met	missense_variant	9/14	ENST00000521913.7
DPYSL2	NM_001386.6	c.854C>T	p.Thr285Met	missense_variant	9/14
DPYSL2	NM_001244604.2	c.746C>T	p.Thr249Met	missense_variant	9/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DPYSL2	ENST00000521913.7	c.1169C>T	p.Thr390Met	missense_variant	9/14	1	NM_001197293.3
DPYSL2	ENST00000311151.9	c.854C>T	p.Thr285Met	missense_variant	9/14	1		P1
DPYSL2	ENST00000523027.1	c.746C>T	p.Thr249Met	missense_variant	9/14	2
DPYSL2	ENST00000474808.1	n.525C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152112 Hom.: 0 Cov.: 32

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

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

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

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

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: 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
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
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.81	D
REVEL	Pathogenic	0.84
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

Other links and lift over

dbSNP: rs199869101; hg19: chr8-26500997;