NM_133625.6:c.-259G>A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_133625.6(SYN2):​c.-259G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 26)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SYN2 NM_133625.6 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.128
• Publications: 0 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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN2	NM_133625.6	c.-259G>A		upstream_gene_variant		ENST00000621198.5	NP_598328.1
SYN2	NM_003178.6	c.-259G>A		upstream_gene_variant			NP_003169.2
SYN2	XM_006713311.4	c.-259G>A		upstream_gene_variant			XP_006713374.1

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 2998 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 1622

African (AFR) AF: 0.00 AC: 0 AN: 224

American (AMR) AF: 0.00 AC: 0 AN: 50

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 108

East Asian (EAS) AF: 0.00 AC: 0 AN: 450

South Asian (SAS) AF: 0.00 AC: 0 AN: 96

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 98

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 26

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1774

Other (OTH) AF: 0.00 AC: 0 AN: 172

GnomAD4 genome Cov.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	5.5
DANN	Benign	0.96
PhyloP100		-0.13
PromoterAI		-0.16	Neutral

Splicing

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

Other links and lift over

dbSNP: rs2623873; hg19: chr3-12045767;