2-26898620-G-A

Position:

• chr2-26898620-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PS1_Moderate PM2

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 Conflicting classifications of pathogenicity (no stars). 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: Conflicting classifications of pathogenicity no assertion criteria provided P:1 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 Uncertain_significance. Variant got 4 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

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: no assertion criteria provided

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Ritscher-Schinzel syndrome 4 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 22, 2021

- -

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;