Genetic Variant SYPL2:p.Thr4Ile (chr1-109466854-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001040709.2(SYPL2):c.11C>T(p.Thr4Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,528,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

SYPL2
NM_001040709.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.60

Variant links:

Genes affected

SYPL2 (HGNC:27638): (synaptophysin like 2) Involved in substantia nigra development. Predicted to be integral component of membrane. Predicted to be active in synaptic vesicle membrane. [provided by Alliance of Genome Resources, Apr 2022]

SYPL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09740314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYPL2	NM_001040709.2 link	c.11C>T	p.Thr4Ile	missense_variant	Exon 1 of 6	ENST00000369872.4	NP_001035799.1	Q5VXT5-1
SYPL2	XM_011541283.3 link	c.11C>T	p.Thr4Ile	missense_variant	Exon 1 of 7		XP_011539585.1
SYPL2	XM_011541284.3 link	c.11C>T	p.Thr4Ile	missense_variant	Exon 1 of 6		XP_011539586.1
SYPL2	XM_011541285.2 link	c.11C>T	p.Thr4Ile	missense_variant	Exon 1 of 5		XP_011539587.1	B4DYR7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYPL2	ENST00000369872.4 link	c.11C>T	p.Thr4Ile	missense_variant	Exon 1 of 6	1	NM_001040709.2	ENSP00000358888.3		Q5VXT5-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000812

AC:

AN:

123170

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

67846

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000104

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1376284

Hom.:

Cov.:

AF XY:

0.00000884

AC XY:

AN XY:

678978

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000287

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000121

Gnomad4 OTH exome

AF:

0.0000174

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.11C>T (p.T4I) alteration is located in exon 1 (coding exon 1) of the SYPL2 gene. This alteration results from a C to T substitution at nucleotide position 11, causing the threonine (T) at amino acid position 4 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.41

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.048

Eigen

Benign

0.10

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.53

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.097

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.73

REVEL

Benign

0.066

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.28

Vest4

0.27

MutPred

0.17

Loss of glycosylation at T4 (P = 0.0127);

MVP

0.15

MPC

0.27

ClinPred

0.73

GERP RS

3.8

Varity_R

0.27

gMVP

0.56

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over