NM_001197293.3:c.355-4690C>G

Variant names:

• chr8-26577279-C-G
• rs431246
• NM_001197293.3:c.355-4690C>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 publications found

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]

DPYSL2 Gene-Disease associations (from GenCC):

• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001197293.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPYSL2	NM_001197293.3	MANE Select	c.355-4690C>G		intron	N/A	NP_001184222.1	A0A1C7CYX9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPYSL2	ENST00000521913.7	TSL:1 MANE Select	c.355-4690C>G		intron	N/A	ENSP00000427985.2	A0A1C7CYX9
	DPYSL2	ENST00000493789.6	TSL:4	c.167C>G	p.Pro56Arg	missense	Exon 1 of 3	ENSP00000427954.1	E5RFU4

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

GnomAD2 exomes AF: 0.341 AC: 6872 AN: 20144 AF XY: 0.339

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 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

African (AFR) AF: 0.314 AC: 477 AN: 1520

American (AMR) AF: 0.315 AC: 1312 AN: 4170

Ashkenazi Jewish (ASJ) AF: 0.279 AC: 1154 AN: 4130

East Asian (EAS) AF: 0.204 AC: 226 AN: 1108

South Asian (SAS) AF: 0.363 AC: 14195 AN: 39130

European-Finnish (FIN) AF: 0.260 AC: 2272 AN: 8742

Middle Eastern (MID) AF: 0.247 AC: 166 AN: 672

European-Non Finnish (NFE) AF: 0.251 AC: 24544 AN: 97624

Other (OTH) AF: 0.259 AC: 1997 AN: 7706

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

African (AFR) AF: 0.302 AC: 12481 AN: 41392

American (AMR) AF: 0.259 AC: 3946 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 915 AN: 3468

East Asian (EAS) AF: 0.192 AC: 978 AN: 5082

South Asian (SAS) AF: 0.384 AC: 1853 AN: 4828

European-Finnish (FIN) AF: 0.257 AC: 2690 AN: 10452

Middle Eastern (MID) AF: 0.301 AC: 88 AN: 292

European-Non Finnish (NFE) AF: 0.244 AC: 16522 AN: 67670

Other (OTH) AF: 0.257 AC: 539 AN: 2100

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
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
PhyloP100		0.71
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
PromoterAI		-0.15	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

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