NM_182961.4:c.2653T>G

Variant names:

Variant summary

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

The NM_182961.4(SYNE1):c.2653T>G(p.Leu885Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0592 in 1,614,058 control chromosomes in the GnomAD database, including 3,084 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.059 ( 309 hom., cov: 33)

Exomes 𝑓: 0.059 ( 2775 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.06

Publications

24 publications found

Variant links:

Genes affected

SYNE1 (HGNC:17089): (spectrin repeat containing nuclear envelope protein 1) This gene encodes a spectrin repeat containing protein expressed in skeletal and smooth muscle, and peripheral blood lymphocytes, that localizes to the nuclear membrane. Mutations in this gene have been associated with autosomal recessive spinocerebellar ataxia 8, also referred to as autosomal recessive cerebellar ataxia type 1 or recessive ataxia of Beauce. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

SYNE1 Gene-Disease associations (from GenCC):

autosomal recessive ataxia, Beauce type
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
arthrogryposis multiplex congenita 3, myogenic type
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Emery-Dreifuss muscular dystrophy 4, autosomal dominant
Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
autosomal dominant Emery-Dreifuss muscular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive myogenic arthrogryposis multiplex congenita
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SYNE1 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=0.0016322136).

BP6

Variant 6-152455960-A-C is Benign according to our data. Variant chr6-152455960-A-C is described in ClinVar as [Benign]. Clinvar id is 130437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0663 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4 link	c.2653T>G	p.Leu885Val	missense_variant	Exon 23 of 146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10 link	c.2653T>G	p.Leu885Val	missense_variant	Exon 23 of 146	1	NM_182961.4	ENSP00000356224.5		Q8NF91-1

Frequencies

GnomAD3 genomes

AF:

0.0588

AC:

8950

AN:

152138

Hom.:

305

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0516

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0568

Gnomad ASJ

AF:

0.105

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.0448

Gnomad FIN

AF:

0.0531

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0679

Gnomad OTH

AF:

0.0737

GnomAD2 exomes

AF:

0.0548

AC:

13784

AN:

251376

AF XY:

0.0560

show subpopulations

Gnomad AFR exome

AF:

0.0544

Gnomad AMR exome

AF:

0.0351

Gnomad ASJ exome

AF:

0.109

Gnomad EAS exome

AF:

0.000924

Gnomad FIN exome

AF:

0.0568

Gnomad NFE exome

AF:

0.0666

Gnomad OTH exome

AF:

0.0610

GnomAD4 exome

AF:

0.0592

AC:

86517

AN:

1461802

Hom.:

2775

Cov.:

AF XY:

0.0591

AC XY:

42982

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.0543

AC:

1818

AN:

33480

American (AMR)

AF:

0.0375

AC:

1678

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.108

AC:

2825

AN:

26130

East Asian (EAS)

AF:

0.000328

AC:

AN:

39692

South Asian (SAS)

AF:

0.0452

AC:

3903

AN:

86256

European-Finnish (FIN)

AF:

0.0544

AC:

2905

AN:

53396

Middle Eastern (MID)

AF:

0.0648

AC:

374

AN:

5768

European-Non Finnish (NFE)

AF:

0.0624

AC:

69349

AN:

1111964

Other (OTH)

AF:

0.0605

AC:

3652

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

4593

9186

13779

18372

22965

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2474

4948

7422

9896

12370

<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:

0.0589

AC:

8966

AN:

152256

Hom.:

309

Cov.:

AF XY:

0.0575

AC XY:

4283

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0519

AC:

2156

AN:

41540

American (AMR)

AF:

0.0567

AC:

867

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

363

AN:

3470

East Asian (EAS)

AF:

0.00174

AC:

AN:

5186

South Asian (SAS)

AF:

0.0446

AC:

215

AN:

4816

European-Finnish (FIN)

AF:

0.0531

AC:

564

AN:

10620

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0679

AC:

4619

AN:

68014

Other (OTH)

AF:

0.0724

AC:

153

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

436

871

1307

1742

2178

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

200

300

400

500

<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:

0.0628

Hom.:

772

Bravo

AF:

0.0581

TwinsUK

AF:

0.0604

AC:

224

ALSPAC

AF:

0.0584

AC:

225

ESP6500AA

AF:

0.0545

AC:

240

ESP6500EA

AF:

0.0679

AC:

584

ExAC

AF:

0.0556

AC:

6747

Asia WGS

AF:

0.0360

AC:

123

AN:

3478

EpiCase

AF:

0.0680

EpiControl

AF:

0.0680

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Jan 30, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Dec 18, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive ataxia, Beauce type

Benign:1

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. -

Emery-Dreifuss muscular dystrophy 4, autosomal dominant

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

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

0.058

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.21

T;.;T;.;.;.;T

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.63

T;T;T;T;T;T;T

MetaRNN

Benign

0.0016

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;.;.;L;.;L;.

PhyloP100

2.1

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.67

N;.;N;N;N;N;N

REVEL

Benign

0.028

Sift

Benign

0.24

T;.;T;T;T;T;T

Sift4G

Benign

0.28

T;T;T;T;T;T;T

Polyphen

0.055

B;.;.;B;B;.;B

Vest4

0.040

MPC

0.13

ClinPred

0.0029

GERP RS

1.5

Varity_R

0.048

gMVP

0.065

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

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