3-12140656-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_133625.6(SYN2):c.383A>G(p.Lys128Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00225 in 761,966 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00083 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (30 hom.)
• Consequence: SYN2 NM_133625.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.85

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009096175).
• BP6: Variant 3-12140656-A-G is Benign according to our data. Variant chr3-12140656-A-G is described in ClinVar as [Benign]. Clinvar id is 3038848.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000834 (127/152292) while in subpopulation SAS AF= 0.0255 (123/4824). AF 95% confidence interval is 0.0218. There are 2 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYN2	NM_133625.6	c.383A>G	p.Lys128Arg	missense_variant	2/13	ENST00000621198.5
SYN2	NM_003178.6	c.383A>G	p.Lys128Arg	missense_variant	2/11
SYN2	XM_006713311.4	c.383A>G	p.Lys128Arg	missense_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYN2	ENST00000621198.5	c.383A>G	p.Lys128Arg	missense_variant	2/13	1	NM_133625.6	P2
SYN2	ENST00000620175.4	c.383A>G	p.Lys128Arg	missense_variant	2/11	1		A2
SYN2	ENST00000424884.1	n.132A>G		non_coding_transcript_exon_variant	2/5	4

Frequencies

GnomAD3 genomes AF: 0.000828 AC: 126 AN: 152174 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0253

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00282 AC: 622 AN: 220940 Hom.: 11 AF XY: 0.00393 AC XY: 466 AN XY: 118484

Gnomad AFR exome AF: 0.000150

Gnomad AMR exome AF: 0.0000638

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0228

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000204

Gnomad OTH exome AF: 0.00145

GnomAD4 exome AF: 0.00261 AC: 1589 AN: 609674 Hom.: 30 Cov.: 0 AF XY: 0.00379 AC XY: 1252 AN XY: 330636

Gnomad4 AFR exome AF: 0.0000571

Gnomad4 AMR exome AF: 0.0000488

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000588

Gnomad4 OTH exome AF: 0.000832

GnomAD4 genome AF: 0.000834 AC: 127 AN: 152292 Hom.: 2 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74464

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0255

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000332 Hom.: 0

Bravo AF: 0.000185

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00305 AC: 368

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

SYN2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2019

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	0.073
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.010
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.53	D;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D
MetaRNN	Benign	0.0091	T;T
MetaSVM	Benign	-0.60	T
MutationTaster	Benign	0.92	N
PrimateAI	Pathogenic	0.80	T
Sift4G	Uncertain	0.026	D;T
Polyphen		0.96	D;P
Vest4		0.57
MutPred		0.73		Loss of methylation at K128 (P = 0.0063);Loss of methylation at K128 (P = 0.0063);
MVP		0.27
ClinPred		0.20	T
GERP RS		4.3
Varity_R		0.40
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs544852588; hg19: chr3-12182156;