8-26581971-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP5_Moderate

The NM_001197293.3(DPYSL2):c.357C>A(p.Ser119Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S119S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DPYSL2 NM_001197293.3 missense, splice_region
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.457

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 where missense usually causes diseases, DPYSL2
• PP5: Variant 8-26581971-C-A is Pathogenic according to our data. Variant chr8-26581971-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225088.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DPYSL2	NM_001197293.3	c.357C>A	p.Ser119Arg	missense_variant, splice_region_variant	2/14	ENST00000521913.7
DPYSL2	NM_001386.6	c.42C>A	p.Ser14Arg	missense_variant, splice_region_variant	2/14
DPYSL2	NM_001244604.2	c.-67C>A		splice_region_variant, 5_prime_UTR_variant	2/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DPYSL2	ENST00000521913.7	c.357C>A	p.Ser119Arg	missense_variant, splice_region_variant	2/14	1	NM_001197293.3
DPYSL2	ENST00000311151.9	c.42C>A	p.Ser14Arg	missense_variant, splice_region_variant	2/14	1		P1
DPYSL2	ENST00000493789.6	c.258C>A	p.Ser86Arg	missense_variant, splice_region_variant	2/3	4
DPYSL2	ENST00000523027.1	c.-67C>A		splice_region_variant, 5_prime_UTR_variant	2/14	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Benign	16
Dann	Benign	0.97
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Uncertain	0.71	D;D;D
MetaSVM	Uncertain	0.42	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
Polyphen		1.0	.;.;D
Vest4		0.80
MutPred		0.43		.;.;Loss of sheet (P = 0.0228);
MVP		0.96
MPC		2.8
ClinPred		0.99	D
GERP RS		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.74
gMVP		0.91

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

LitVar

Other links and lift over

dbSNP: rs138340807; hg19: chr8-26439487;