3-12187515-A-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_133625.6(SYN2):​c.1516A>T​(p.Thr506Ser) variant causes a missense 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. 11/16 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T506A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SYN2 NM_133625.6 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12522346).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN2	NM_133625.6	c.1516A>T	p.Thr506Ser	missense_variant	Exon 12 of 13	ENST00000621198.5	NP_598328.1
SYN2	XM_006713312.5	c.1033A>T	p.Thr345Ser	missense_variant	Exon 9 of 10		XP_006713375.1
SYN2	XM_017007087.2	c.844A>T	p.Thr282Ser	missense_variant	Exon 8 of 9		XP_016862576.1
SYN2	XM_006713313.3	c.745A>T	p.Thr249Ser	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>T	p.Thr506Ser	missense_variant	Exon 12 of 13	1	NM_133625.6	ENSP00000480050.1
SYN2	ENST00000439861.5	n.1135A>T		non_coding_transcript_exon_variant	Exon 9 of 10	2
ENSG00000288952	ENST00000690965.2	n.527+4853T>A		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1400702 Hom.: 0 Cov.: 88 AF XY: 0.00 AC XY: 0 AN XY: 690892

African (AFR) AF: 0.00 AC: 0 AN: 31664

American (AMR) AF: 0.00 AC: 0 AN: 35800

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25222

East Asian (EAS) AF: 0.00 AC: 0 AN: 35872

South Asian (SAS) AF: 0.00 AC: 0 AN: 79328

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49456

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1079534

Other (OTH) AF: 0.00 AC: 0 AN: 58126

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 31370

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	0.0019	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Benign	0.81
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.020
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.90	T
PhyloP100		1.7
PrimateAI	Uncertain	0.58	T
Sift4G	Benign	0.73	T
Vest4		0.068
ClinPred		0.94	D
GERP RS		2.5
Varity_R		0.097
gMVP		0.085
Mutation Taster		=99/1	polymorphism

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;