rs4902264

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.5906T>C(p.Met1969Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.848 in 1,613,774 control chromosomes in the GnomAD database, including 589,138 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1969I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.73 ( 43964 hom., cov: 32)

Exomes 𝑓: 0.86 ( 545174 hom. )

Consequence

SYNE2
NM_182914.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.0370

Publications

39 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=7.5595824E-7).

BP6

Variant 14-64024977-T-C is Benign according to our data. Variant chr14-64024977-T-C is described in ClinVar as Benign. ClinVar VariationId is 130501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.873 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3 link	c.5906T>C	p.Met1969Thr	missense_variant	Exon 40 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.5906T>C	p.Met1969Thr	missense_variant	Exon 40 of 116	1	NM_182914.3	ENSP00000450831.2		Q8WXH0-2A0A0C4DGK3

Frequencies

GnomAD3 genomes

AF:

0.734

AC:

111623

AN:

152004

Hom.:

43963

Cov.:

show subpopulations

Gnomad AFR

AF:

0.423

Gnomad AMI

AF:

0.884

Gnomad AMR

AF:

0.776

Gnomad ASJ

AF:

0.791

Gnomad EAS

AF:

0.792

Gnomad SAS

AF:

0.803

Gnomad FIN

AF:

0.865

Gnomad MID

AF:

0.722

Gnomad NFE

AF:

0.879

Gnomad OTH

AF:

0.755

GnomAD2 exomes

AF:

0.816

AC:

203604

AN:

249398

AF XY:

0.825

show subpopulations

Gnomad AFR exome

AF:

0.407

Gnomad AMR exome

AF:

0.803

Gnomad ASJ exome

AF:

0.774

Gnomad EAS exome

AF:

0.788

Gnomad FIN exome

AF:

0.873

Gnomad NFE exome

AF:

0.876

Gnomad OTH exome

AF:

0.815

GnomAD4 exome

AF:

0.860

AC:

1256367

AN:

1461654

Hom.:

545174

Cov.:

AF XY:

0.859

AC XY:

624734

AN XY:

727128

show subpopulations

African (AFR)

AF:

0.391

AC:

13086

AN:

33466

American (AMR)

AF:

0.799

AC:

35722

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.777

AC:

20306

AN:

26128

East Asian (EAS)

AF:

0.777

AC:

30812

AN:

39664

South Asian (SAS)

AF:

0.813

AC:

70128

AN:

86256

European-Finnish (FIN)

AF:

0.876

AC:

46806

AN:

53418

Middle Eastern (MID)

AF:

0.786

AC:

4528

AN:

5764

European-Non Finnish (NFE)

AF:

0.886

AC:

985116

AN:

1111864

Other (OTH)

AF:

0.826

AC:

49863

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

9630

19261

28891

38522

48152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21274

42548

63822

85096

106370

<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:

0.734

AC:

111639

AN:

152120

Hom.:

43964

Cov.:

AF XY:

0.735

AC XY:

54638

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.423

AC:

17519

AN:

41464

American (AMR)

AF:

0.776

AC:

11862

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.791

AC:

2746

AN:

3472

East Asian (EAS)

AF:

0.792

AC:

4097

AN:

5172

South Asian (SAS)

AF:

0.804

AC:

3881

AN:

4828

European-Finnish (FIN)

AF:

0.865

AC:

9155

AN:

10586

Middle Eastern (MID)

AF:

0.724

AC:

213

AN:

294

European-Non Finnish (NFE)

AF:

0.879

AC:

59773

AN:

68004

Other (OTH)

AF:

0.754

AC:

1587

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1237

2474

3710

4947

6184

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

822

1644

2466

3288

4110

<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:

0.827

Hom.:

174991

Bravo

AF:

0.712

TwinsUK

AF:

0.883

AC:

3275

ALSPAC

AF:

0.878

AC:

3383

ESP6500AA

AF:

0.444

AC:

1642

ESP6500EA

AF:

0.875

AC:

7155

ExAC

AF:

0.811

AC:

98029

Asia WGS

AF:

0.763

AC:

2655

AN:

3478

EpiCase

AF:

0.875

EpiControl

AF:

0.867

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 14, 2018

Athena Diagnostics

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

- -

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. -

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

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

0.12

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.014

.;T;T;T

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.44

T;T;T;T

MetaRNN

Benign

7.6e-7

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.69

N;.;N;.

PhyloP100

-0.037

PrimateAI

Benign

0.35

PROVEAN

Benign

1.1

N;.;N;N

REVEL

Benign

0.035

Sift

Benign

1.0

T;.;T;T

Sift4G

Benign

0.091

T;D;T;D

Polyphen

0.0030

B;.;B;.

Vest4

0.13

MPC

0.053

ClinPred

0.0035

GERP RS

-1.3

Varity_R

0.035

gMVP

0.077

Mutation Taster

=295/5

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