chr3-12187515-A-G

Variant names:

Variant summary

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

The NM_133625.6(SYN2):c.1516A>G(p.Thr506Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.744 in 1,552,224 control chromosomes in the GnomAD database, including 432,406 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.70 ( 37742 hom., cov: 29)

Exomes 𝑓: 0.75 ( 394664 hom. )

Consequence

SYN2
NM_133625.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.70

Publications

34 publications found

Variant links:

Genes affected

SYN2 (HGNC:11495): (synapsin II) This gene is a member of the synapsin gene family. Synapsins encode neuronal phosphoproteins which associate with the cytoplasmic surface of synaptic vesicles. Family members are characterized by common protein domains, and they are implicated in synaptogenesis and the modulation of neurotransmitter release, suggesting a potential role in several neuropsychiatric diseases. This member of the synapsin family encodes a neuron-specific phosphoprotein that selectively binds to small synaptic vesicles in the presynaptic nerve terminal. Polymorphisms in this gene are associated with abnormal presynaptic function and related neuronal disorders, including autism, epilepsy, bipolar disorder and schizophrenia. Alternative splicing of this gene results in multiple transcript variants. The tissue inhibitor of metalloproteinase 4 gene is located within an intron of this gene and is transcribed in the opposite direction. [provided by RefSeq, Feb 2014]

SYN2 links:

ENSG00000288952 (HGNC:):

ENSG00000288952 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=6.864383E-7).

BP6

Variant 3-12187515-A-G is Benign according to our data. Variant chr3-12187515-A-G is described in ClinVar as Benign. ClinVar VariationId is 1298153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.769 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN2	NM_133625.6 link	c.1516A>G	p.Thr506Ala	missense_variant	Exon 12 of 13	ENST00000621198.5	NP_598328.1	Q92777-1Q86VA8B3KRB3
SYN2	XM_006713312.5 link	c.1033A>G	p.Thr345Ala	missense_variant	Exon 9 of 10		XP_006713375.1
SYN2	XM_017007087.2 link	c.844A>G	p.Thr282Ala	missense_variant	Exon 8 of 9		XP_016862576.1
SYN2	XM_006713313.3 link	c.745A>G	p.Thr249Ala	missense_variant	Exon 9 of 10		XP_006713376.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SYN2	ENST00000621198.5 link	c.1516A>G	p.Thr506Ala	missense_variant	Exon 12 of 13	1	NM_133625.6	ENSP00000480050.1	Q92777-1
SYN2	ENST00000439861.5 link	n.1135A>G		non_coding_transcript_exon_variant	Exon 9 of 10	2
ENSG00000288952	ENST00000690965.2 link	n.527+4853T>C		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes

AF:

0.699

AC:

105864

AN:

151518

Hom.:

37709

Cov.:

show subpopulations

Gnomad AFR

AF:

0.547

Gnomad AMI

AF:

0.916

Gnomad AMR

AF:

0.766

Gnomad ASJ

AF:

0.729

Gnomad EAS

AF:

0.684

Gnomad SAS

AF:

0.790

Gnomad FIN

AF:

0.791

Gnomad MID

AF:

0.775

Gnomad NFE

AF:

0.749

Gnomad OTH

AF:

0.738

GnomAD2 exomes

AF:

0.762

AC:

118931

AN:

156012

AF XY:

0.764

show subpopulations

Gnomad AFR exome

AF:

0.542

Gnomad AMR exome

AF:

0.854

Gnomad ASJ exome

AF:

0.733

Gnomad EAS exome

AF:

0.688

Gnomad FIN exome

AF:

0.787

Gnomad NFE exome

AF:

0.749

Gnomad OTH exome

AF:

0.769

GnomAD4 exome

AF:

0.749

AC:

1049306

AN:

1400588

Hom.:

394664

Cov.:

AF XY:

0.750

AC XY:

518431

AN XY:

690830

show subpopulations

African (AFR)

AF:

0.538

AC:

17045

AN:

31664

American (AMR)

AF:

0.846

AC:

30275

AN:

35798

Ashkenazi Jewish (ASJ)

AF:

0.738

AC:

18621

AN:

25220

East Asian (EAS)

AF:

0.670

AC:

24020

AN:

35870

South Asian (SAS)

AF:

0.804

AC:

63806

AN:

79314

European-Finnish (FIN)

AF:

0.778

AC:

38456

AN:

49456

Middle Eastern (MID)

AF:

0.805

AC:

4589

AN:

5700

European-Non Finnish (NFE)

AF:

0.749

AC:

808938

AN:

1079444

Other (OTH)

AF:

0.749

AC:

43556

AN:

58122

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

17438

34876

52314

69752

87190

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19920

39840

59760

79680

99600

<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:

0.699

AC:

105947

AN:

151636

Hom.:

37742

Cov.:

AF XY:

0.703

AC XY:

52046

AN XY:

74080

show subpopulations

African (AFR)

AF:

0.547

AC:

22547

AN:

41198

American (AMR)

AF:

0.767

AC:

11709

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.729

AC:

2529

AN:

3468

East Asian (EAS)

AF:

0.684

AC:

3482

AN:

5088

South Asian (SAS)

AF:

0.790

AC:

3803

AN:

4814

European-Finnish (FIN)

AF:

0.791

AC:

8345

AN:

10552

Middle Eastern (MID)

AF:

0.776

AC:

228

AN:

294

European-Non Finnish (NFE)

AF:

0.749

AC:

50909

AN:

67926

Other (OTH)

AF:

0.739

AC:

1560

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

1595

3191

4786

6382

7977

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

828

1656

2484

3312

4140

<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:

0.721

Hom.:

31370

Bravo

AF:

0.690

TwinsUK

AF:

0.750

AC:

2782

ALSPAC

AF:

0.729

AC:

2810

ESP6500AA

AF:

0.586

AC:

2232

ESP6500EA

AF:

0.764

AC:

6069

ExAC

AF:

0.669

AC:

54979

Asia WGS

AF:

0.733

AC:

2549

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 21, 2019

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

- -

SYN2-related disorder

Benign:1

Feb 26, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.70

DEOGEN2

Benign

0.11

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.23

MetaRNN

Benign

6.9e-7

MetaSVM

Benign

-1.0

PhyloP100

1.7

PrimateAI

Uncertain

0.58

Sift4G

Benign

0.44

Polyphen

0.0020

Vest4

0.029

ClinPred

0.068

GERP RS

2.5

Varity_R

0.14

gMVP

0.12

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