Genetic Variant NM_133625.6:c.-259G>T (chr3-12004293-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_133625.6(SYN2):c.-259G>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.756 in 153,652 control chromosomes in the GnomAD database, including 46,413 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 0.76 ( 45563 hom., cov: 26)

Exomes 𝑓: 0.63 ( 850 hom. )

Consequence

SYN2
NM_133625.6 upstream_gene

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.128

Publications

2 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:

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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 (BayesDel_noAF=-0.66).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.871 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein	UniProt
SYN2	NM_133625.6 link	c.-259G>T	upstream_gene_variant	ENST00000621198.5	NP_598328.1	Q92777-1Q86VA8B3KRB3
SYN2	NM_003178.6 link	c.-259G>T	upstream_gene_variant		NP_003169.2	Q92777-2Q59GM1
SYN2	XM_006713311.4 link	c.-259G>T	upstream_gene_variant		XP_006713374.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYN2	ENST00000621198.5 link	c.-259G>T		upstream_gene_variant		1	NM_133625.6	ENSP00000480050.1		Q92777-1
SYN2	ENST00000620175.4 link	c.-259G>T		upstream_gene_variant		1		ENSP00000484916.1		Q92777-2

Frequencies

GnomAD3 genomes

AF:

0.759

AC:

114193

AN:

150550

Hom.:

45550

Cov.:

show subpopulations

Gnomad AFR

AF:

0.488

Gnomad AMI

AF:

0.980

Gnomad AMR

AF:

0.829

Gnomad ASJ

AF:

0.779

Gnomad EAS

AF:

0.674

Gnomad SAS

AF:

0.875

Gnomad FIN

AF:

0.906

Gnomad MID

AF:

0.784

Gnomad NFE

AF:

0.877

Gnomad OTH

AF:

0.767

GnomAD4 exome

AF:

0.632

AC:

1890

AN:

2990

Hom.:

850

AF XY:

0.649

AC XY:

1051

AN XY:

1620

show subpopulations

African (AFR)

AF:

0.0804

AC:

AN:

224

American (AMR)

AF:

0.580

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.491

AC:

AN:

108

East Asian (EAS)

AF:

0.255

AC:

113

AN:

444

South Asian (SAS)

AF:

0.958

AC:

AN:

European-Finnish (FIN)

AF:

0.806

AC:

AN:

Middle Eastern (MID)

AF:

0.615

AC:

AN:

European-Non Finnish (NFE)

AF:

0.782

AC:

1386

AN:

1772

Other (OTH)

AF:

0.605

AC:

104

AN:

172

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.527

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.758

AC:

114248

AN:

150662

Hom.:

45563

Cov.:

AF XY:

0.762

AC XY:

56071

AN XY:

73552

show subpopulations

African (AFR)

AF:

0.488

AC:

20033

AN:

41034

American (AMR)

AF:

0.830

AC:

12645

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.779

AC:

2691

AN:

3456

East Asian (EAS)

AF:

0.675

AC:

3249

AN:

4816

South Asian (SAS)

AF:

0.875

AC:

4171

AN:

4766

European-Finnish (FIN)

AF:

0.906

AC:

9456

AN:

10432

Middle Eastern (MID)

AF:

0.769

AC:

223

AN:

290

European-Non Finnish (NFE)

AF:

0.877

AC:

59279

AN:

67624

Other (OTH)

AF:

0.768

AC:

1609

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

1131

2263

3394

4526

5657

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

834

1668

2502

3336

4170

<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:

0.807

Hom.:

6350

Bravo

AF:

0.738

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

2.0

(source)

DANN

Benign

0.93

PhyloP100

-0.13

PromoterAI

0.044

Neutral

(source)

Splicing

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

Computational scores

Splicing

Publications

Other links and lift over