NM_133625.6:c.-259G>T

Variant names:

• chr3-12004293-G-T
• rs2623873
• NM_133625.6:c.-259G>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.128

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]

ACMG classification

Verdict is Benign. Variant got -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	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN2	NM_133625.6	c.-259G>T		upstream_gene_variant		ENST00000621198.5	NP_598328.1
SYN2	NM_003178.6	c.-259G>T		upstream_gene_variant			NP_003169.2
SYN2	XM_006713311.4	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	c.-259G>T		upstream_gene_variant		1	NM_133625.6	ENSP00000480050.1
SYN2	ENST00000620175.4	c.-259G>T		upstream_gene_variant		1		ENSP00000484916.1

Frequencies

GnomAD3 genomes AF: 0.759 AC: 114193 AN: 150550 Hom.: 45550 Cov.: 26

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

Gnomad4 AFR exome AF: 0.0804

Gnomad4 AMR exome AF: 0.580

Gnomad4 ASJ exome AF: 0.491

Gnomad4 EAS exome AF: 0.255

Gnomad4 SAS exome AF: 0.958

Gnomad4 FIN exome AF: 0.806

Gnomad4 NFE exome AF: 0.782

Gnomad4 OTH exome AF: 0.605

GnomAD4 genome AF: 0.758 AC: 114248 AN: 150662 Hom.: 45563 Cov.: 26 AF XY: 0.762 AC XY: 56071 AN XY: 73552

Gnomad4 AFR AF: 0.488

Gnomad4 AMR AF: 0.830

Gnomad4 ASJ AF: 0.779

Gnomad4 EAS AF: 0.675

Gnomad4 SAS AF: 0.875

Gnomad4 FIN AF: 0.906

Gnomad4 NFE AF: 0.877

Gnomad4 OTH AF: 0.768

Alfa AF: 0.788 Hom.: 4552

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
DANN	Benign	0.93

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2623873; hg19: chr3-12045767;