rs17751301

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.4177C>T(p.Arg1393Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0649 in 1,614,050 control chromosomes in the GnomAD database, including 3,992 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. R1393Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.049 ( 243 hom., cov: 32)

Exomes 𝑓: 0.067 ( 3749 hom. )

Consequence

SYNE2
NM_182914.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.03

Publications

19 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=0.0018231869).

BP6

Variant 14-64003110-C-T is Benign according to our data. Variant chr14-64003110-C-T is described in ClinVar as Benign. ClinVar VariationId is 130497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0792 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182914.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	NM_182914.3	MANE Select	c.4177C>T	p.Arg1393Trp	missense	Exon 30 of 116	NP_878918.2
	SYNE2	NM_015180.6		c.4177C>T	p.Arg1393Trp	missense	Exon 30 of 115	NP_055995.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SYNE2	ENST00000555002.6	TSL:1 MANE Select	c.4177C>T	p.Arg1393Trp	missense	Exon 30 of 116	ENSP00000450831.2
SYNE2	ENST00000344113.8	TSL:1	c.4177C>T	p.Arg1393Trp	missense	Exon 30 of 115	ENSP00000341781.4
SYNE2	ENST00000358025.7	TSL:5	c.4177C>T	p.Arg1393Trp	missense	Exon 30 of 116	ENSP00000350719.3

Frequencies

GnomAD3 genomes

AF:

0.0487

AC:

7404

AN:

152156

Hom.:

245

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0118

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0833

Gnomad ASJ

AF:

0.0545

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0207

Gnomad FIN

AF:

0.0373

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0712

Gnomad OTH

AF:

0.0397

GnomAD2 exomes

AF:

0.0602

AC:

14960

AN:

248510

AF XY:

0.0571

show subpopulations

Gnomad AFR exome

AF:

0.0123

Gnomad AMR exome

AF:

0.131

Gnomad ASJ exome

AF:

0.0511

Gnomad EAS exome

AF:

0.000223

Gnomad FIN exome

AF:

0.0424

Gnomad NFE exome

AF:

0.0698

Gnomad OTH exome

AF:

0.0603

GnomAD4 exome

AF:

0.0666

AC:

97319

AN:

1461776

Hom.:

3749

Cov.:

AF XY:

0.0648

AC XY:

47126

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.0102

AC:

341

AN:

33480

American (AMR)

AF:

0.124

AC:

5567

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0523

AC:

1367

AN:

26132

East Asian (EAS)

AF:

0.000126

AC:

AN:

39694

South Asian (SAS)

AF:

0.0207

AC:

1784

AN:

86254

European-Finnish (FIN)

AF:

0.0424

AC:

2265

AN:

53372

Middle Eastern (MID)

AF:

0.0156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0742

AC:

82528

AN:

1111956

Other (OTH)

AF:

0.0558

AC:

3372

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

5165

10329

15494

20658

25823

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3060

6120

9180

12240

15300

<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:

0.0486

AC:

7398

AN:

152274

Hom.:

243

Cov.:

AF XY:

0.0469

AC XY:

3489

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.0117

AC:

487

AN:

41552

American (AMR)

AF:

0.0830

AC:

1271

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0545

AC:

189

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.0205

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0373

AC:

396

AN:

10612

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0712

AC:

4842

AN:

68008

Other (OTH)

AF:

0.0393

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

374

747

1121

1494

1868

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

234

312

390

<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:

0.0619

Hom.:

1461

Bravo

AF:

0.0522

TwinsUK

AF:

0.0720

AC:

267

ALSPAC

AF:

0.0677

AC:

261

ESP6500AA

AF:

0.0132

AC:

ESP6500EA

AF:

0.0707

AC:

580

ExAC

AF:

0.0562

AC:

6792

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.0661

EpiControl

AF:

0.0620

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Emery-Dreifuss muscular dystrophy 5, autosomal dominant (2)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.58

CADD

Benign

1.5

(source)

DANN

Benign

0.19

DEOGEN2

Benign

0.025

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0018

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

-1.0

PrimateAI

Benign

0.17

PROVEAN

Benign

-1.2

REVEL

Benign

0.064

Sift

Benign

0.060

Sift4G

Benign

0.19

Polyphen

0.0020

Vest4

0.13

MPC

0.049

ClinPred

0.0038

GERP RS

-3.2

Varity_R

0.039

gMVP

0.074

Mutation Taster

=298/2

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over