chr14-64031176-C-A

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.7040C>A(p.Ala2347Glu) 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 1,614,134 control chromosomes in the GnomAD database, including 751 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2347S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.037 ( 326 hom., cov: 33)

Exomes 𝑓: 0.0059 ( 425 hom. )

Consequence

SYNE2
NM_182914.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.61

Publications

7 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=0.001334846).

BP6

Variant 14-64031176-C-A is Benign according to our data. Variant chr14-64031176-C-A is described in ClinVar as Benign. ClinVar VariationId is 130506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
SYNE2	NM_182914.3 link	c.7040C>A	p.Ala2347Glu	missense_variant	Exon 45 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.7040C>A	p.Ala2347Glu	missense_variant	Exon 45 of 116	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes

AF:

0.0365

AC:

5557

AN:

152186

Hom.:

323

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

GnomAD2 exomes

AF:

0.0116

AC:

2896

AN:

249400

AF XY:

0.00981

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000283

Gnomad OTH exome

AF:

0.00528

GnomAD4 exome

AF:

0.00585

AC:

8557

AN:

1461832

Hom.:

425

Cov.:

AF XY:

0.00561

AC XY:

4080

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.136

AC:

4554

AN:

33466

American (AMR)

AF:

0.00749

AC:

335

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0372

AC:

1475

AN:

39692

South Asian (SAS)

AF:

0.0139

AC:

1196

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00624

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000285

AC:

317

AN:

1111988

Other (OTH)

AF:

0.0107

AC:

644

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

435

870

1305

1740

2175

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

182

364

546

728

910

<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:

0.0366

AC:

5579

AN:

152302

Hom.:

326

Cov.:

AF XY:

0.0354

AC XY:

2638

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.123

AC:

5113

AN:

41548

American (AMR)

AF:

0.0144

AC:

221

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0148

AC:

AN:

5188

South Asian (SAS)

AF:

0.0155

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000397

AC:

AN:

68026

Other (OTH)

AF:

0.0293

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

243

487

730

974

1217

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0158

Hom.:

221

Bravo

AF:

0.0414

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.120

AC:

440

ESP6500EA

AF:

0.000610

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

Oct 29, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Emery-Dreifuss muscular dystrophy 5, autosomal dominant

Benign:3

Feb 03, 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. -

Apr 07, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

SYNE2-related disorder

Benign:1

Jan 31, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

0.060

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Benign

0.52

DEOGEN2

Benign

0.0030

.;T;T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.018

LIST_S2

Benign

0.31

T;T;T;T

MetaRNN

Benign

0.0013

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.90

N;.;N;.

PhyloP100

1.6

PrimateAI

Benign

0.23

PROVEAN

Benign

1.1

N;.;N;N

REVEL

Benign

0.080

Sift

Benign

0.99

T;.;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

B;.;B;.

Vest4

0.054

MPC

0.053

ClinPred

0.00073

GERP RS

1.2

Varity_R

0.023

gMVP

0.10

Mutation Taster

=99/1

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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