Genetic Variant NM_133625.6:c.775-2140C>T (chr3-12159406-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBA1

The NM_133625.6(SYN2):c.775-2140C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 152,724 control chromosomes in the GnomAD database, including 8,763 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 0.31 ( 8710 hom., cov: 32)

Exomes 𝑓: 0.34 ( 53 hom. )

Consequence

SYN2
NM_133625.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.651

Publications

30 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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.627 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN2	NM_133625.6 link	c.775-2140C>T		intron_variant	Intron 5 of 12	ENST00000621198.5	NP_598328.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein
SYN2	ENST00000621198.5 link	c.775-2140C>T	intron_variant	Intron 5 of 12	1	NM_133625.6	ENSP00000480050.1
SYN2	ENST00000620175.4 link	c.775-2140C>T	intron_variant	Intron 5 of 10	1		ENSP00000484916.1
SYN2	ENST00000439861.5 link	n.226-2140C>T	intron_variant	Intron 2 of 9	2
SYN2	ENST00000447752.2 link	n.223+535C>T	intron_variant	Intron 1 of 4	4

Frequencies

GnomAD3 genomes

AF:

0.315

AC:

47799

AN:

151916

Hom.:

8707

Cov.:

show subpopulations

Gnomad AFR

AF:

0.158

Gnomad AMI

AF:

0.529

Gnomad AMR

AF:

0.336

Gnomad ASJ

AF:

0.313

Gnomad EAS

AF:

0.646

Gnomad SAS

AF:

0.562

Gnomad FIN

AF:

0.466

Gnomad MID

AF:

0.348

Gnomad NFE

AF:

0.336

Gnomad OTH

AF:

0.319

GnomAD4 exome

AF:

0.339

AC:

233

AN:

688

Hom.:

AF XY:

0.339

AC XY:

131

AN XY:

386

show subpopulations

African (AFR)

AF:

0.250

AC:

AN:

American (AMR)

AF:

0.200

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.667

AC:

AN:

East Asian (EAS)

AF:

0.556

AC:

AN:

South Asian (SAS)

AF:

0.594

AC:

AN:

European-Finnish (FIN)

AF:

0.278

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.322

AC:

163

AN:

506

Other (OTH)

AF:

0.357

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

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:

0.315

AC:

47816

AN:

152036

Hom.:

8710

Cov.:

AF XY:

0.329

AC XY:

24440

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.158

AC:

6539

AN:

41500

American (AMR)

AF:

0.336

AC:

5134

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.313

AC:

1087

AN:

3472

East Asian (EAS)

AF:

0.646

AC:

3312

AN:

5130

South Asian (SAS)

AF:

0.562

AC:

2705

AN:

4814

European-Finnish (FIN)

AF:

0.466

AC:

4929

AN:

10572

Middle Eastern (MID)

AF:

0.347

AC:

102

AN:

294

European-Non Finnish (NFE)

AF:

0.336

AC:

22843

AN:

67952

Other (OTH)

AF:

0.324

AC:

683

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1585

3170

4755

6340

7925

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

480

960

1440

1920

2400

<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:

0.328

Hom.:

26083

Bravo

AF:

0.293

Asia WGS

AF:

0.564

AC:

1962

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

0.65

PromoterAI

-0.052

Neutral

(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

Computational scores

Splicing

Publications

Other links and lift over