rs2228979

Variant names:

• chr8-26624181-G-A
• rs2228979
• NM_001197293.3:c.667G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-26624181-G-A
• chr8-26624181-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001197293.3(DPYSL2):​c.667G>A​(p.Ala223Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.002 in 1,614,186 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (98 hom.)
• Consequence: DPYSL2 NM_001197293.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.236
• Publications: 11 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036204457).
• BP6: Variant 8-26624181-G-A is Benign according to our data. Variant chr8-26624181-G-A is described in ClinVar as Benign. ClinVar VariationId is 708360.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0672 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPYSL2	NM_001197293.3	MANE Select	c.667G>A	p.Ala223Thr	missense	Exon 4 of 14	NP_001184222.1
	DPYSL2	NM_001386.6		c.352G>A	p.Ala118Thr	missense	Exon 4 of 14	NP_001377.1
	DPYSL2	NM_001244604.2		c.244G>A	p.Ala82Thr	missense	Exon 4 of 14	NP_001231533.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DPYSL2	ENST00000521913.7	TSL:1 MANE Select	c.667G>A	p.Ala223Thr	missense	Exon 4 of 14	ENSP00000427985.2
	DPYSL2	ENST00000311151.9	TSL:1	c.352G>A	p.Ala118Thr	missense	Exon 4 of 14	ENSP00000309539.5
	DPYSL2	ENST00000523027.1	TSL:2	c.244G>A	p.Ala82Thr	missense	Exon 4 of 14	ENSP00000431117.1

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 430 AN: 152180 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0733

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00644 AC: 1620 AN: 251410 AF XY: 0.00605

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0842

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00191 AC: 2791 AN: 1461888 Hom.: 98 Cov.: 29 AF XY: 0.00190 AC XY: 1379 AN XY: 727246

African (AFR) AF: 0.000119 AC: 4 AN: 33478

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26136

East Asian (EAS) AF: 0.0583 AC: 2316 AN: 39700

South Asian (SAS) AF: 0.00137 AC: 118 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000136 AC: 151 AN: 1112010

Other (OTH) AF: 0.00313 AC: 189 AN: 60394

GnomAD4 genome AF: 0.00282 AC: 430 AN: 152298 Hom.: 13 Cov.: 32 AF XY: 0.00333 AC XY: 248 AN XY: 74474

African (AFR) AF: 0.000217 AC: 9 AN: 41564

American (AMR) AF: 0.000458 AC: 7 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.0733 AC: 379 AN: 5172

South Asian (SAS) AF: 0.00311 AC: 15 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68022

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00257 Hom.: 37

Bravo AF: 0.00397

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00595 AC: 722

Asia WGS AF: 0.0240 AC: 85 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	11
DANN	Benign	0.89
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.83	L
PhyloP100		0.24
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.14
Sift	Benign	0.19	T
Sift4G	Benign	0.23	T
Polyphen		0.078	B
Vest4		0.078
MVP		0.28
MPC		0.82
ClinPred		0.0045	T
GERP RS		2.6
Varity_R		0.15
gMVP		0.57
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs2228979; hg19: chr8-26481697; COSMIC: COSV60783601; COSMIC: COSV60783601;