8-26583915-G-A

Variant names:

• chr8-26583915-G-A
• NM_001197293.3:c.560G>A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001197293.3(DPYSL2):​c.560G>A​(p.Gly187Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: DPYSL2 NM_001197293.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.872

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPYSL2	NM_001197293.3	c.560G>A	p.Gly187Glu	missense_variant	Exon 3 of 14	ENST00000521913.7	NP_001184222.1
DPYSL2	NM_001386.6	c.245G>A	p.Gly82Glu	missense_variant	Exon 3 of 14		NP_001377.1
DPYSL2	NM_001244604.2	c.137G>A	p.Gly46Glu	missense_variant	Exon 3 of 14		NP_001231533.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPYSL2	ENST00000521913.7	c.560G>A	p.Gly187Glu	missense_variant	Exon 3 of 14	1	NM_001197293.3	ENSP00000427985.2
DPYSL2	ENST00000311151.9	c.245G>A	p.Gly82Glu	missense_variant	Exon 3 of 14	1		ENSP00000309539.5
DPYSL2	ENST00000523027.1	c.137G>A	p.Gly46Glu	missense_variant	Exon 3 of 14	2		ENSP00000431117.1
DPYSL2	ENST00000493789.6	c.461G>A	p.Gly154Glu	missense_variant	Exon 3 of 3	4		ENSP00000427954.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.560G>A (p.G187E) alteration is located in exon 3 (coding exon 3) of the DPYSL2 gene. This alteration results from a G to A substitution at nucleotide position 560, causing the glycine (G) at amino acid position 187 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	0.33
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	.;T;D;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Uncertain	2.7	.;.;M;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.9	.;D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	.;D;D;D
Sift4G	Uncertain	0.0020	.;D;D;D
Polyphen		1.0	.;.;D;.
Vest4		0.91
MutPred		0.58		.;.;Gain of solvent accessibility (P = 0.1045);.;
MVP		0.95
MPC		2.2
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.96
gMVP		0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-26441431;