8-26624306-C-T

Position:

• chr8-26624306-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_001197293.3(DPYSL2):​c.792C>T​(p.His264=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00369 in 1,613,984 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0038 (12 hom.)
• Consequence: DPYSL2 NM_001197293.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.002138
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.702

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 8-26624306-C-T is Benign according to our data. Variant chr8-26624306-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 718924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.702 with no splicing effect.
• BS2: High AC in GnomAd4 at 444 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPYSL2	NM_001197293.3	c.792C>T	p.His264=	splice_region_variant, synonymous_variant	4/14	ENST00000521913.7	NP_001184222.1
DPYSL2	NM_001386.6	c.477C>T	p.His159=	splice_region_variant, synonymous_variant	4/14		NP_001377.1
DPYSL2	NM_001244604.2	c.369C>T	p.His123=	splice_region_variant, synonymous_variant	4/14		NP_001231533.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPYSL2	ENST00000521913.7	c.792C>T	p.His264=	splice_region_variant, synonymous_variant	4/14	1	NM_001197293.3	ENSP00000427985
DPYSL2	ENST00000311151.9	c.477C>T	p.His159=	splice_region_variant, synonymous_variant	4/14	1		ENSP00000309539	P1
DPYSL2	ENST00000523027.1	c.369C>T	p.His123=	splice_region_variant, synonymous_variant	4/14	2		ENSP00000431117
DPYSL2	ENST00000523093.5	n.458C>T		splice_region_variant, non_coding_transcript_exon_variant	1/5	2

Frequencies

GnomAD3 genomes AF: 0.00291 AC: 443 AN: 152210 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00414

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00434

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00319 AC: 800 AN: 250758 Hom.: 3 AF XY: 0.00321 AC XY: 435 AN XY: 135476

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00997

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.00458

Gnomad NFE exome AF: 0.00415

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00377 AC: 5508 AN: 1461656 Hom.: 12 Cov.: 33 AF XY: 0.00366 AC XY: 2664 AN XY: 727110

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.00266

Gnomad4 ASJ exome AF: 0.00981

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.00421

Gnomad4 NFE exome AF: 0.00417

Gnomad4 OTH exome AF: 0.00359

GnomAD4 genome AF: 0.00291 AC: 444 AN: 152328 Hom.: 1 Cov.: 32 AF XY: 0.00271 AC XY: 202 AN XY: 74486

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00414

Gnomad4 NFE AF: 0.00434

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00373 Hom.: 3

Bravo AF: 0.00260

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00387

EpiControl AF: 0.00480

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	DPYSL2: BP4, BP7, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	1.7
DANN	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0021
dbscSNV1_RF	Benign	0.064
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

LitVar

Other links and lift over

dbSNP: rs139123217; hg19: chr8-26481822;