rs2254562

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_203446.3(SYNJ1):c.884A>G(p.Lys295Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.279 in 1,530,650 control chromosomes in the GnomAD database, including 61,131 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K295Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.29 ( 6568 hom., cov: 32)

Exomes 𝑓: 0.28 ( 54563 hom. )

Consequence

SYNJ1
NM_203446.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 7.68

Publications

43 publications found

Variant links:

Genes affected

SYNJ1 (HGNC:11503): (synaptojanin 1) This gene encodes a phosphoinositide phosphatase that regulates levels of membrane phosphatidylinositol-4,5-bisphosphate. As such, expression of this enzyme may affect synaptic transmission and membrane trafficking. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

SYNJ1 Gene-Disease associations (from GenCC):

genetic developmental and epileptic encephalopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 53
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
early-onset Parkinson disease 20
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
undetermined early-onset epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
atypical juvenile parkinsonism
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
young-onset Parkinson disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SYNJ1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017498434).

BP6

Variant 21-32687042-T-C is Benign according to our data. Variant chr21-32687042-T-C is described in ClinVar as Benign. ClinVar VariationId is 586758.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNJ1	NM_203446.3 link	c.884A>G	p.Lys295Arg	missense_variant	Exon 8 of 33	ENST00000674351.1	NP_982271.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNJ1	ENST00000674351.1 link	c.884A>G	p.Lys295Arg	missense_variant	Exon 8 of 33		NM_203446.3	ENSP00000501530.1

Frequencies

GnomAD3 genomes

AF:

0.292

AC:

44433

AN:

151940

Hom.:

6560

Cov.:

show subpopulations

Gnomad AFR

AF:

0.305

Gnomad AMI

AF:

0.245

Gnomad AMR

AF:

0.280

Gnomad ASJ

AF:

0.398

Gnomad EAS

AF:

0.347

Gnomad SAS

AF:

0.314

Gnomad FIN

AF:

0.227

Gnomad MID

AF:

0.370

Gnomad NFE

AF:

0.286

Gnomad OTH

AF:

0.315

GnomAD2 exomes

AF:

0.276

AC:

54049

AN:

195550

AF XY:

0.281

show subpopulations

Gnomad AFR exome

AF:

0.287

Gnomad AMR exome

AF:

0.238

Gnomad ASJ exome

AF:

0.392

Gnomad EAS exome

AF:

0.307

Gnomad FIN exome

AF:

0.223

Gnomad NFE exome

AF:

0.273

Gnomad OTH exome

AF:

0.284

GnomAD4 exome

AF:

0.278

AC:

383206

AN:

1378592

Hom.:

54563

Cov.:

AF XY:

0.280

AC XY:

192049

AN XY:

686456

show subpopulations

African (AFR)

AF:

0.293

AC:

8371

AN:

28570

American (AMR)

AF:

0.254

AC:

7236

AN:

28520

Ashkenazi Jewish (ASJ)

AF:

0.399

AC:

9548

AN:

23948

East Asian (EAS)

AF:

0.346

AC:

12355

AN:

35706

South Asian (SAS)

AF:

0.311

AC:

23188

AN:

74542

European-Finnish (FIN)

AF:

0.232

AC:

12222

AN:

52586

Middle Eastern (MID)

AF:

0.350

AC:

1951

AN:

5568

European-Non Finnish (NFE)

AF:

0.272

AC:

291580

AN:

1072100

Other (OTH)

AF:

0.294

AC:

16755

AN:

57052

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

11745

23490

35234

46979

58724

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9778

19556

29334

39112

48890

<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:

0.292

AC:

44460

AN:

152058

Hom.:

6568

Cov.:

AF XY:

0.292

AC XY:

21671

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.305

AC:

12624

AN:

41450

American (AMR)

AF:

0.281

AC:

4286

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.398

AC:

1380

AN:

3470

East Asian (EAS)

AF:

0.347

AC:

1792

AN:

5158

South Asian (SAS)

AF:

0.314

AC:

1512

AN:

4816

European-Finnish (FIN)

AF:

0.227

AC:

2404

AN:

10582

Middle Eastern (MID)

AF:

0.354

AC:

104

AN:

294

European-Non Finnish (NFE)

AF:

0.286

AC:

19468

AN:

67988

Other (OTH)

AF:

0.316

AC:

667

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1588

3176

4764

6352

7940

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

458

916

1374

1832

2290

<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:

0.293

Hom.:

23542

Bravo

AF:

0.298

TwinsUK

AF:

0.285

AC:

1055

ALSPAC

AF:

0.281

AC:

1083

ESP6500AA

AF:

0.297

AC:

1307

ESP6500EA

AF:

0.298

AC:

2559

ExAC

AF:

0.292

AC:

35398

Asia WGS

AF:

0.303

AC:

1054

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Early-onset Parkinson disease 20;C4479313:Developmental and epileptic encephalopathy, 53

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

.;T;.;T;T;.

Eigen

Uncertain

0.45

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.69

T;T;T;T;T;T

MetaRNN

Benign

0.0017

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;.;.;.;.;.

PhyloP100

7.7

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.6

N;N;.;N;N;N

REVEL

Benign

0.25

Sift

Benign

0.040

D;T;.;D;T;T

Sift4G

Benign

0.20

T;T;T;T;T;.

Polyphen

0.99

D;.;.;B;.;.

Vest4

0.37

MPC

1.3

ClinPred

0.021

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.26

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over