rs794999

Variant names:

• chr3-12187515-A-G
• rs794999
• NM_133625.6:c.1516A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-12187515-A-G
• chr3-12187515-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.70
• Publications: 34 publications found

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]

ENSG00000288952 (HGNC:):

ACMG classification

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	c.1516A>G	p.Thr506Ala	missense_variant	Exon 12 of 13	ENST00000621198.5	NP_598328.1
SYN2	XM_006713312.5	c.1033A>G	p.Thr345Ala	missense_variant	Exon 9 of 10		XP_006713375.1
SYN2	XM_017007087.2	c.844A>G	p.Thr282Ala	missense_variant	Exon 8 of 9		XP_016862576.1
SYN2	XM_006713313.3	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	Appris	UniProt
SYN2	ENST00000621198.5	c.1516A>G	p.Thr506Ala	missense_variant	Exon 12 of 13	1	NM_133625.6	ENSP00000480050.1
SYN2	ENST00000439861.5	n.1135A>G		non_coding_transcript_exon_variant	Exon 9 of 10	2
ENSG00000288952	ENST00000690965.2	n.527+4853T>C		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes AF: 0.699 AC: 105864 AN: 151518 Hom.: 37709 Cov.: 29

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

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.: 88 AF XY: 0.750 AC XY: 518431 AN XY: 690830

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

GnomAD4 genome AF: 0.699 AC: 105947 AN: 151636 Hom.: 37742 Cov.: 29 AF XY: 0.703 AC XY: 52046 AN XY: 74080

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

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

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	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Benign	0.70
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.23	T
MetaRNN	Benign	6.9e-7	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.7
PrimateAI	Uncertain	0.58	T
Sift4G	Benign	0.44	T
Polyphen		0.0020	B
Vest4		0.029
ClinPred		0.068	T
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

Other links and lift over

dbSNP: rs794999; hg19: chr3-12229015; COSMIC: COSV101413855; COSMIC: COSV101413855;