Variant 4-119027358-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_133477.3(SYNPO2):c.989C>T(p.Ser330Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,116 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S330P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

SYNPO2
NM_133477.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.32

Variant links:

Genes affected

SYNPO2 (HGNC:17732): (synaptopodin 2) Enables alpha-actinin binding activity and filamin binding activity. Involved in positive regulation of actin filament bundle assembly; positive regulation of cell migration; and regulation of Rho-dependent protein serine/threonine kinase activity. Located in several cellular components, including Z disc; focal adhesion; and stress fiber. [provided by Alliance of Genome Resources, Apr 2022]

SYNPO2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a modified_residue Phosphoserine (size 0) in uniprot entity SYNP2_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24942869).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNPO2	NM_133477.3 linkuse as main transcript	c.989C>T	p.Ser330Leu	missense_variant	3/5	ENST00000307142.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNPO2	ENST00000307142.9 linkuse as main transcript	c.989C>T	p.Ser330Leu	missense_variant	3/5	1	NM_133477.3	P1	Q9UMS6-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74306

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2024

The c.989C>T (p.S330L) alteration is located in exon 3 (coding exon 3) of the SYNPO2 gene. This alteration results from a C to T substitution at nucleotide position 989, causing the serine (S) at amino acid position 330 to be replaced by a leucine (L). 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

0.12

BayesDel_addAF

Benign

0.0025

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.034

.;.;T;.

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Benign

0.023

MetaRNN

Benign

0.25

T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.0

.;M;M;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.4

.;N;N;N

REVEL

Benign

0.23

Sift

Uncertain

0.0010

.;D;D;D

Sift4G

Uncertain

0.010

D;D;D;D

Polyphen

0.99, 0.99

.;D;D;.

Vest4

0.34

MutPred

0.13

.;Loss of phosphorylation at S330 (P = 0.0143);Loss of phosphorylation at S330 (P = 0.0143);Loss of phosphorylation at S330 (P = 0.0143);

MVP

0.082

MPC

0.23

ClinPred

0.95

GERP RS

5.7

Varity_R

0.24

gMVP

0.17

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

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