rs34843668

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_182914.3(SYNE2):c.9078A>T(p.Glu3026Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0286 in 1,610,852 control chromosomes in the GnomAD database, including 889 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 101 hom., cov: 33)

Exomes 𝑓: 0.029 ( 788 hom. )

Consequence

SYNE2
NM_182914.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.965

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

autosomal dominant Emery-Dreifuss muscular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Emery-Dreifuss muscular dystrophy 5, autosomal dominant
Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics
left ventricular noncompaction
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

SYNE2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002384305).

BP6

Variant 14-64052991-A-T is Benign according to our data. Variant chr14-64052991-A-T is described in ClinVar as Benign. ClinVar VariationId is 130518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3 link	c.9078A>T	p.Glu3026Asp	missense_variant	Exon 48 of 116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6 link	c.9078A>T	p.Glu3026Asp	missense_variant	Exon 48 of 116	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes

AF:

0.0294

AC:

4467

AN:

152186

Hom.:

101

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00765

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0649

Gnomad ASJ

AF:

0.0150

Gnomad EAS

AF:

0.0494

Gnomad SAS

AF:

0.0102

Gnomad FIN

AF:

0.0609

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0309

Gnomad OTH

AF:

0.0263

GnomAD2 exomes

AF:

0.0360

AC:

8829

AN:

245360

AF XY:

0.0330

show subpopulations

Gnomad AFR exome

AF:

0.00774

Gnomad AMR exome

AF:

0.0858

Gnomad ASJ exome

AF:

0.0142

Gnomad EAS exome

AF:

0.0488

Gnomad FIN exome

AF:

0.0520

Gnomad NFE exome

AF:

0.0280

Gnomad OTH exome

AF:

0.0302

GnomAD4 exome

AF:

0.0285

AC:

41577

AN:

1458548

Hom.:

788

Cov.:

AF XY:

0.0279

AC XY:

20214

AN XY:

725274

show subpopulations

African (AFR)

AF:

0.00690

AC:

229

AN:

33202

American (AMR)

AF:

0.0834

AC:

3678

AN:

44080

Ashkenazi Jewish (ASJ)

AF:

0.0134

AC:

348

AN:

26064

East Asian (EAS)

AF:

0.0524

AC:

2079

AN:

39670

South Asian (SAS)

AF:

0.0110

AC:

933

AN:

84824

European-Finnish (FIN)

AF:

0.0503

AC:

2684

AN:

53368

Middle Eastern (MID)

AF:

0.00400

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0270

AC:

30040

AN:

1111320

Other (OTH)

AF:

0.0259

AC:

1563

AN:

60264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

2304

4609

6913

9218

11522

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1128

2256

3384

4512

5640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0293

AC:

4466

AN:

152304

Hom.:

101

Cov.:

AF XY:

0.0308

AC XY:

2297

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00762

AC:

317

AN:

41578

American (AMR)

AF:

0.0648

AC:

991

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

AN:

3472

East Asian (EAS)

AF:

0.0494

AC:

256

AN:

5186

South Asian (SAS)

AF:

0.0102

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0609

AC:

647

AN:

10620

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0308

AC:

2098

AN:

68026

Other (OTH)

AF:

0.0260

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

213

426

639

852

1065

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0283

Hom.:

Bravo

AF:

0.0283

TwinsUK

AF:

0.0270

AC:

100

ALSPAC

AF:

0.0259

AC:

100

ESP6500AA

AF:

0.0114

AC:

ESP6500EA

AF:

0.0257

AC:

209

ExAC

AF:

0.0327

AC:

3951

Asia WGS

AF:

0.0300

AC:

104

AN:

3476

EpiCase

AF:

0.0226

EpiControl

AF:

0.0238

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 14, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Emery-Dreifuss muscular dystrophy 5, autosomal dominant

Benign:3

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 specified

Benign:2

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.031

.;T;T;T

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.49

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.83

T;T;T;T

MetaRNN

Benign

0.0024

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;.;L;.

PhyloP100

0.96

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.7

N;.;N;N

REVEL

Benign

0.059

Sift

Benign

0.030

D;.;D;D

Sift4G

Benign

0.082

T;D;T;D

Polyphen

0.63

P;.;P;.

Vest4

0.15

MutPred

0.094

Loss of ubiquitination at K3027 (P = 0.0642);.;Loss of ubiquitination at K3027 (P = 0.0642);.;

MPC

0.18

ClinPred

0.021

GERP RS

-0.54

Varity_R

0.087

gMVP

0.075

Mutation Taster

=284/16

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over