8-26624290-C-A

Variant names:

• chr8-26624290-C-A
• NM_001197293.3:c.776C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_001197293.3(DPYSL2):​c.776C>A​(p.Ala259Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DPYSL2 NM_001197293.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.13

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 2 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity DPYL2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24088752).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPYSL2	NM_001197293.3	c.776C>A	p.Ala259Glu	missense_variant	Exon 4 of 14	ENST00000521913.7	NP_001184222.1
DPYSL2	NM_001386.6	c.461C>A	p.Ala154Glu	missense_variant	Exon 4 of 14		NP_001377.1
DPYSL2	NM_001244604.2	c.353C>A	p.Ala118Glu	missense_variant	Exon 4 of 14		NP_001231533.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPYSL2	ENST00000521913.7	c.776C>A	p.Ala259Glu	missense_variant	Exon 4 of 14	1	NM_001197293.3	ENSP00000427985.2
DPYSL2	ENST00000311151.9	c.461C>A	p.Ala154Glu	missense_variant	Exon 4 of 14	1		ENSP00000309539.5
DPYSL2	ENST00000523027.1	c.353C>A	p.Ala118Glu	missense_variant	Exon 4 of 14	2		ENSP00000431117.1
DPYSL2	ENST00000523093.5	n.442C>A		non_coding_transcript_exon_variant	Exon 1 of 5	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.776C>A (p.A259E) alteration is located in exon 4 (coding exon 4) of the DPYSL2 gene. This alteration results from a C to A substitution at nucleotide position 776, causing the alanine (A) at amino acid position 259 to be replaced by a glutamic acid (E). 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	0.21
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.37	.;T;.
Eigen	Benign	-0.067
Eigen_PC	Benign	0.064
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Uncertain	-0.092	T
MutationAssessor	Benign	0.96	.;L;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.4	.;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.46	.;T;T
Sift4G	Benign	0.69	.;T;T
Polyphen		0.76	.;P;.
Vest4		0.44, 0.43
MutPred		0.55		.;Gain of disorder (P = 0.0123);.;
MVP		0.58
MPC		1.0
ClinPred		0.51	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.88

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-26481806;