rs7157465

Positions:

chr14-64031211-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000555002.6(SYNE2):c.7075A>G(p.Ser2359Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00876 in 1,614,154 control chromosomes in the GnomAD database, including 752 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S2359N) has been classified as Benign.

Frequency

Genomes: 𝑓 0.037 ( 327 hom., cov: 33)

Exomes 𝑓: 0.0059 ( 425 hom. )

Consequence

SYNE2
ENST00000555002.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.68

Variant links:

Genes affected

SYNE2 (HGNC:17084): (spectrin repeat containing nuclear envelope protein 2) The protein encoded by this gene is a nuclear outer membrane protein that binds cytoplasmic F-actin. This binding tethers the nucleus to the cytoskeleton and aids in the maintenance of the structural integrity of the nucleus. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

SYNE2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016507208).

BP6

Variant 14-64031211-A-G is Benign according to our data. Variant chr14-64031211-A-G is described in ClinVar as [Benign]. Clinvar id is 130507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64031211-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE2	NM_182914.3 linkuse as main transcript	c.7075A>G	p.Ser2359Gly	missense_variant	45/116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6 linkuse as main transcript	c.7075A>G	p.Ser2359Gly	missense_variant	45/116	1	NM_182914.3	ENSP00000450831	P4	Q8WXH0-2

Frequencies

GnomAD3 genomes

AF:

0.0365

AC:

5557

AN:

152188

Hom.:

324

Cov.:

show subpopulations

Gnomad AFR

AF:

0.123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0145

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0148

Gnomad SAS

AF:

0.0157

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.0263

GnomAD3 exomes

AF:

0.0116

AC:

2895

AN:

249390

Hom.:

126

AF XY:

0.00981

AC XY:

1328

AN XY:

135312

show subpopulations

Gnomad AFR exome

AF:

0.131

Gnomad AMR exome

AF:

0.00730

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00884

Gnomad SAS exome

AF:

0.0130

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000283

Gnomad OTH exome

AF:

0.00528

GnomAD4 exome

AF:

0.00586

AC:

8563

AN:

1461848

Hom.:

425

Cov.:

AF XY:

0.00561

AC XY:

4083

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.136

Gnomad4 AMR exome

AF:

0.00751

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0372

Gnomad4 SAS exome

AF:

0.0139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000285

Gnomad4 OTH exome

AF:

0.0107

GnomAD4 genome

AF:

0.0366

AC:

5579

AN:

152306

Hom.:

327

Cov.:

AF XY:

0.0354

AC XY:

2638

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.123

Gnomad4 AMR

AF:

0.0144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0148

Gnomad4 SAS

AF:

0.0155

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.0293

Alfa

AF:

0.00817

Hom.:

Bravo

AF:

0.0414

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.120

AC:

446

ESP6500EA

AF:

0.000608

AC:

ExAC

AF:

0.0144

AC:

1736

Asia WGS

AF:

0.0320

AC:

110

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 22, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Emery-Dreifuss muscular dystrophy 5, autosomal dominant

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Apr 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

SYNE2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2020

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

0.075

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.029

.;T;T;T

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.83

T;T;T;T

MetaRNN

Benign

0.0017

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

M;.;M;.

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.6

N;.;N;N

REVEL

Benign

0.081

Sift

Benign

0.037

D;.;D;D

Sift4G

Uncertain

0.040

D;D;D;D

Polyphen

0.0040

B;.;B;.

Vest4

0.085

MPC

0.047

ClinPred

0.013

GERP RS

2.7

Varity_R

0.055

gMVP

0.11

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