rs9944035

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.1721T>C(p.Ile574Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0776 in 1,593,248 control chromosomes in the GnomAD database, including 5,821 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.092 ( 699 hom., cov: 32)

Exomes 𝑓: 0.076 ( 5122 hom. )

Consequence

SYNE2
NM_182914.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.30

Publications

25 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=0.0016518831).

BP6

Variant 14-63981058-T-C is Benign according to our data. Variant chr14-63981058-T-C is described in ClinVar as Benign. ClinVar VariationId is 130486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3 link	c.1721T>C	p.Ile574Thr	missense_variant	Exon 16 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.1721T>C	p.Ile574Thr	missense_variant	Exon 16 of 116	1	NM_182914.3	ENSP00000450831.2		Q8WXH0-2A0A0C4DGK3

Frequencies

GnomAD3 genomes

AF:

0.0920

AC:

13987

AN:

152034

Hom.:

700

Cov.:

show subpopulations

Gnomad AFR

AF:

0.113

Gnomad AMI

AF:

0.00879

Gnomad AMR

AF:

0.113

Gnomad ASJ

AF:

0.135

Gnomad EAS

AF:

0.108

Gnomad SAS

AF:

0.173

Gnomad FIN

AF:

0.0790

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.0680

Gnomad OTH

AF:

0.105

GnomAD2 exomes

AF:

0.101

AC:

25062

AN:

249116

AF XY:

0.103

show subpopulations

Gnomad AFR exome

AF:

0.109

Gnomad AMR exome

AF:

0.125

Gnomad ASJ exome

AF:

0.147

Gnomad EAS exome

AF:

0.119

Gnomad FIN exome

AF:

0.0815

Gnomad NFE exome

AF:

0.0712

Gnomad OTH exome

AF:

0.105

GnomAD4 exome

AF:

0.0761

AC:

109645

AN:

1441096

Hom.:

5122

Cov.:

AF XY:

0.0788

AC XY:

56618

AN XY:

718200

show subpopulations

African (AFR)

AF:

0.113

AC:

3742

AN:

32992

American (AMR)

AF:

0.125

AC:

5599

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.149

AC:

3867

AN:

25988

East Asian (EAS)

AF:

0.110

AC:

4354

AN:

39524

South Asian (SAS)

AF:

0.159

AC:

13623

AN:

85498

European-Finnish (FIN)

AF:

0.0826

AC:

4411

AN:

53378

Middle Eastern (MID)

AF:

0.134

AC:

768

AN:

5728

European-Non Finnish (NFE)

AF:

0.0622

AC:

67978

AN:

1093626

Other (OTH)

AF:

0.0889

AC:

5303

AN:

59684

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

5413

10826

16240

21653

27066

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2598

5196

7794

10392

12990

<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:

0.0919

AC:

13985

AN:

152152

Hom.:

699

Cov.:

AF XY:

0.0951

AC XY:

7071

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.112

AC:

4669

AN:

41512

American (AMR)

AF:

0.113

AC:

1731

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.135

AC:

469

AN:

3470

East Asian (EAS)

AF:

0.108

AC:

561

AN:

5180

South Asian (SAS)

AF:

0.173

AC:

835

AN:

4826

European-Finnish (FIN)

AF:

0.0790

AC:

836

AN:

10584

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0680

AC:

4623

AN:

67980

Other (OTH)

AF:

0.102

AC:

216

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

649

1298

1946

2595

3244

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

344

516

688

860

<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:

0.0802

Hom.:

2353

Bravo

AF:

0.0941

TwinsUK

AF:

0.0628

AC:

233

ALSPAC

AF:

0.0571

AC:

220

ESP6500AA

AF:

0.106

AC:

381

ESP6500EA

AF:

0.0705

AC:

574

ExAC

AF:

0.0992

AC:

11986

Asia WGS

AF:

0.131

AC:

454

AN:

3476

EpiCase

AF:

0.0823

EpiControl

AF:

0.0841

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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. -

Oct 29, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 12, 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 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.47

DEOGEN2

Benign

0.063

.;T;T;T

Eigen

Benign

0.13

Eigen_PC

Benign

0.048

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.73

T;T;T;T

MetaRNN

Benign

0.0017

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;.;L;.

PhyloP100

3.3

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.5

D;.;D;D

REVEL

Benign

0.15

Sift

Benign

0.040

D;.;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

0.95

P;.;P;.

Vest4

0.34

MPC

0.069

ClinPred

0.038

GERP RS

5.6

Varity_R

0.11

gMVP

0.18

Mutation Taster

=296/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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