3-12004712-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_133625.6(SYN2):c.161C>T(p.Ala54Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00405 in 146,058 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0041 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0055 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: SYN2 NM_133625.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0620

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00633502).
• BP6: Variant 3-12004712-C-T is Benign according to our data. Variant chr3-12004712-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2653538.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYN2	NM_133625.6	c.161C>T	p.Ala54Val	missense_variant	1/13	ENST00000621198.5
SYN2	NM_003178.6	c.161C>T	p.Ala54Val	missense_variant	1/11
SYN2	XM_006713311.4	c.161C>T	p.Ala54Val	missense_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYN2	ENST00000621198.5	c.161C>T	p.Ala54Val	missense_variant	1/13	1	NM_133625.6	P2
SYN2	ENST00000620175.4	c.161C>T	p.Ala54Val	missense_variant	1/11	1		A2

Frequencies

GnomAD3 genomes AF: 0.00405 AC: 592 AN: 146010 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000476

Gnomad ASJ AF: 0.0100

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0187

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00573

Gnomad OTH AF: 0.00350

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00546 AC: 136 AN: 24890 Hom.: 1 Cov.: 0 AF XY: 0.00513 AC XY: 71 AN XY: 13842

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00120

Gnomad4 ASJ exome AF: 0.00641

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0168

Gnomad4 NFE exome AF: 0.00472

Gnomad4 OTH exome AF: 0.00299

GnomAD4 genome AF: 0.00405 AC: 592 AN: 146058 Hom.: 7 Cov.: 31 AF XY: 0.00446 AC XY: 317 AN XY: 71028

Gnomad4 AFR AF: 0.000245

Gnomad4 AMR AF: 0.000475

Gnomad4 ASJ AF: 0.0100

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0187

Gnomad4 NFE AF: 0.00573

Gnomad4 OTH AF: 0.00347

Alfa AF: 0.0114 Hom.: 18

Bravo AF: 0.00223

ExAC AF: 0.00907 AC: 9

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2023

SYN2: PP3, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	6.7
Dann	Uncertain	0.98
DEOGEN2	Benign	0.17	T;.
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.48	T;T
MetaRNN	Benign	0.0063	T;T
MutationTaster	Benign	0.73	N
PrimateAI	Pathogenic	0.83	D
Sift4G	Benign	0.47	T;T
Vest4		0.065
MVP		0.46
GERP RS		0.16
Varity_R		0.022
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs747241247; hg19: chr3-12046186;