rs431246

Positions:

• chr8-26577279-C-G
• chr8-26577279-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001197293.3(DPYSL2):​c.355-4690C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 316,228 control chromosomes in the GnomAD database, including 11,678 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.27 (5453 hom., cov: 31)
  • Exomes 𝑓: 0.28 (6225 hom.)
• Consequence: DPYSL2 NM_001197293.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.712

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002074629).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPYSL2	NM_001197293.3	c.355-4690C>G		intron_variant		ENST00000521913.7	NP_001184222.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPYSL2	ENST00000521913.7	c.355-4690C>G		intron_variant		1	NM_001197293.3	ENSP00000427985.2
DPYSL2	ENST00000493789.6	c.167C>G	p.Pro56Arg	missense_variant	1/3	4		ENSP00000427954.1

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40164 AN: 151318 Hom.: 5446 Cov.: 31

Gnomad AFR AF: 0.302

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.384

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.299

Gnomad NFE AF: 0.244

Gnomad OTH AF: 0.255

GnomAD3 exomes AF: 0.341 AC: 6872 AN: 20144 Hom.: 808 AF XY: 0.339 AC XY: 4293 AN XY: 12648

Gnomad AFR exome AF: 0.385

Gnomad AMR exome AF: 0.334

Gnomad ASJ exome AF: 0.319

Gnomad EAS exome AF: 0.285

Gnomad SAS exome AF: 0.408

Gnomad FIN exome AF: 0.338

Gnomad NFE exome AF: 0.310

Gnomad OTH exome AF: 0.291

GnomAD4 exome AF: 0.281 AC: 46343 AN: 164802 Hom.: 6225 Cov.: 0 AF XY: 0.291 AC XY: 28656 AN XY: 98586

Gnomad4 AFR exome AF: 0.314

Gnomad4 AMR exome AF: 0.315

Gnomad4 ASJ exome AF: 0.279

Gnomad4 EAS exome AF: 0.204

Gnomad4 SAS exome AF: 0.363

Gnomad4 FIN exome AF: 0.260

Gnomad4 NFE exome AF: 0.251

Gnomad4 OTH exome AF: 0.259

GnomAD4 genome AF: 0.265 AC: 40192 AN: 151426 Hom.: 5453 Cov.: 31 AF XY: 0.268 AC XY: 19805 AN XY: 73950

Gnomad4 AFR AF: 0.302

Gnomad4 AMR AF: 0.259

Gnomad4 ASJ AF: 0.264

Gnomad4 EAS AF: 0.192

Gnomad4 SAS AF: 0.384

Gnomad4 FIN AF: 0.257

Gnomad4 NFE AF: 0.244

Gnomad4 OTH AF: 0.257

Alfa AF: 0.135 Hom.: 250

Bravo AF: 0.264

TwinsUK AF: 0.241 AC: 894

ALSPAC AF: 0.244 AC: 942

ExAC AF: 0.268 AC: 2630

Asia WGS AF: 0.284 AC: 979 AN: 3442

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	6.7
DANN	Benign	0.64
DEOGEN2	Benign	0.0050	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.070
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.040	D
ClinPred		0.027	T
GERP RS		0.84

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs431246; hg19: chr8-26434795; COSMIC: COSV60784164; COSMIC: COSV60784164;