Genetic Variant SYPL2:p.Glu99Gly (chr1-109476817-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001040709.2(SYPL2):c.296A>G(p.Glu99Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0551 in 1,614,138 control chromosomes in the GnomAD database, including 2,873 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.047 ( 205 hom., cov: 32)

Exomes 𝑓: 0.056 ( 2668 hom. )

Consequence

SYPL2
NM_001040709.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.857

Publications

18 publications found

Variant links:

Genes affected

SYPL2 (HGNC:27638): (synaptophysin like 2) Involved in substantia nigra development. Predicted to be integral component of membrane. Predicted to be active in synaptic vesicle membrane. [provided by Alliance of Genome Resources, Apr 2022]

SYPL2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018308759).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0625 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040709.2. 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
	SYPL2	NM_001040709.2	MANE Select	c.296A>G	p.Glu99Gly	missense	Exon 4 of 6	NP_001035799.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYPL2	ENST00000369872.4	TSL:1 MANE Select	c.296A>G	p.Glu99Gly	missense	Exon 4 of 6	ENSP00000358888.3
	SYPL2	ENST00000475497.1	TSL:3	n.506A>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.0465

AC:

7081

AN:

152158

Hom.:

205

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0264

Gnomad AMI

AF:

0.0735

Gnomad AMR

AF:

0.0221

Gnomad ASJ

AF:

0.0156

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.0556

Gnomad FIN

AF:

0.0778

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0641

Gnomad OTH

AF:

0.0307

GnomAD2 exomes

AF:

0.0478

AC:

11914

AN:

249458

AF XY:

0.0499

show subpopulations

Gnomad AFR exome

AF:

0.0263

Gnomad AMR exome

AF:

0.0130

Gnomad ASJ exome

AF:

0.0177

Gnomad EAS exome

AF:

0.00150

Gnomad FIN exome

AF:

0.0731

Gnomad NFE exome

AF:

0.0641

Gnomad OTH exome

AF:

0.0444

GnomAD4 exome

AF:

0.0560

AC:

81838

AN:

1461862

Hom.:

2668

Cov.:

AF XY:

0.0564

AC XY:

41022

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.0267

AC:

895

AN:

33480

American (AMR)

AF:

0.0134

AC:

600

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0165

AC:

431

AN:

26136

East Asian (EAS)

AF:

0.000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0556

AC:

4799

AN:

86256

European-Finnish (FIN)

AF:

0.0716

AC:

3822

AN:

53414

Middle Eastern (MID)

AF:

0.0147

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0614

AC:

68239

AN:

1111992

Other (OTH)

AF:

0.0486

AC:

2937

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

4722

9443

14165

18886

23608

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2414

4828

7242

9656

12070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0465

AC:

7087

AN:

152276

Hom.:

205

Cov.:

AF XY:

0.0477

AC XY:

3550

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0265

AC:

1102

AN:

41562

American (AMR)

AF:

0.0221

AC:

338

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0156

AC:

AN:

3470

East Asian (EAS)

AF:

0.00173

AC:

AN:

5192

South Asian (SAS)

AF:

0.0556

AC:

268

AN:

4820

European-Finnish (FIN)

AF:

0.0778

AC:

824

AN:

10594

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0641

AC:

4358

AN:

68020

Other (OTH)

AF:

0.0304

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

349

698

1048

1397

1746

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

258

344

430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0564

Hom.:

544

Bravo

AF:

0.0399

TwinsUK

AF:

0.0580

AC:

215

ALSPAC

AF:

0.0592

AC:

228

ESP6500AA

AF:

0.0267

AC:

109

ESP6500EA

AF:

0.0567

AC:

475

ExAC

AF:

0.0513

AC:

6203

Asia WGS

AF:

0.0400

AC:

140

AN:

3478

EpiCase

AF:

0.0541

EpiControl

AF:

0.0505

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.026

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.55

MetaRNN

Benign

0.0018

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.34

PhyloP100

0.86

PrimateAI

Benign

0.35

PROVEAN

Benign

1.3

REVEL

Benign

0.023

Sift

Benign

0.57

Sift4G

Benign

0.44

Polyphen

0.0

Vest4

0.092

MPC

0.24

ClinPred

0.0030

GERP RS

3.3

Varity_R

0.063

gMVP

0.51

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over