2-26898620-G-A

Variant names:

• chr2-26898620-G-A
• rs866373727
• NM_020134.4:c.121G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS1_Moderate PM2 PP5_Moderate

The NM_020134.4(DPYSL5):​c.121G>A​(p.Glu41Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DPYSL5 NM_020134.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 U:2
• Conservation: PhyloP100: 3.94

Genes affected

DPYSL5 (HGNC:20637): (dihydropyrimidinase like 5) This gene encodes a member of the CRMP (collapsing response mediator protein) family thought to be involved in neural development. Antibodies to the encoded protein were found in some patients with neurologic symptoms who had paraneoplastic syndrome. A pseudogene of this gene is found on chromosome 11. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PS1: Transcript NM_020134.4 (DPYSL5) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-26898620-G-A is Pathogenic according to our data. Variant chr2-26898620-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1184280.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-26898620-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPYSL5	NM_020134.4	c.121G>A	p.Glu41Lys	missense_variant	Exon 2 of 13	ENST00000288699.11	NP_064519.2
DPYSL5	NM_001253723.2	c.121G>A	p.Glu41Lys	missense_variant	Exon 2 of 13		NP_001240652.1
DPYSL5	NM_001253724.2	c.121G>A	p.Glu41Lys	missense_variant	Exon 2 of 13		NP_001240653.1
DPYSL5	XM_024453007.2	c.121G>A	p.Glu41Lys	missense_variant	Exon 2 of 13		XP_024308775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPYSL5	ENST00000288699.11	c.121G>A	p.Glu41Lys	missense_variant	Exon 2 of 13	1	NM_020134.4	ENSP00000288699.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1 Uncertain:2

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DPYSL5: PS2:Very Strong, PM2, PS4:Moderate, PS3:Supporting -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Ritscher-Schinzel syndrome 4 Pathogenic:1

Jul 22, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	.;T;T;T;T;.
Eigen	Benign	-0.030
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D;.;.;D;D;D
M_CAP	Benign	0.023	T
MetaRNN	Uncertain	0.50	D;D;D;D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.51	.;N;N;.;N;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.7	N;N;N;N;.;N
REVEL	Uncertain	0.39
Sift	Benign	0.062	T;T;T;T;.;T
Sift4G	Uncertain	0.057	T;T;T;D;T;D
Polyphen		0.012	.;B;B;.;B;.
Vest4		0.40, 0.40
MutPred		0.65		Gain of methylation at E41 (P = 0.0206);Gain of methylation at E41 (P = 0.0206);Gain of methylation at E41 (P = 0.0206);Gain of methylation at E41 (P = 0.0206);Gain of methylation at E41 (P = 0.0206);Gain of methylation at E41 (P = 0.0206);
MVP		0.54
MPC		1.1
ClinPred		0.86	D
GERP RS		4.8
Varity_R		0.60
gMVP		0.94

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: rs866373727; hg19: chr2-27121488; COSMIC: COSV56512143;