rs17082236

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_182961.4(SYNE1):c.24502G>T(p.Ala8168Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0602 in 1,613,862 control chromosomes in the GnomAD database, including 5,404 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A8168D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.12 ( 1995 hom., cov: 32)

Exomes 𝑓: 0.054 ( 3409 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.57

Publications

18 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:

ENSG00000300811 (HGNC:):

ENSG00000300811 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=0.0038188696).

BP6

Variant 6-152149617-C-A is Benign according to our data. Variant chr6-152149617-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4 link	c.24502G>T	p.Ala8168Ser	missense_variant	Exon 136 of 146	ENST00000367255.10	NP_892006.3
SYNE1	NM_001347702.2 link	c.967G>T	p.Ala323Ser	missense_variant	Exon 7 of 18	ENST00000354674.5	NP_001334631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10 link	c.24502G>T	p.Ala8168Ser	missense_variant	Exon 136 of 146	1	NM_182961.4	ENSP00000356224.5		Q8NF91-1
SYNE1	ENST00000354674.5 link	c.967G>T	p.Ala323Ser	missense_variant	Exon 7 of 18	5	NM_001347702.2	ENSP00000346701.4		F8WAI0

Frequencies

GnomAD3 genomes

AF:

0.119

AC:

18087

AN:

151924

Hom.:

1993

Cov.:

show subpopulations

Gnomad AFR

AF:

0.290

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0937

Gnomad ASJ

AF:

0.117

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.0278

Gnomad FIN

AF:

0.0404

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.0495

Gnomad OTH

AF:

0.127

GnomAD2 exomes

AF:

0.0646

AC:

16253

AN:

251452

AF XY:

0.0597

show subpopulations

Gnomad AFR exome

AF:

0.298

Gnomad AMR exome

AF:

0.0560

Gnomad ASJ exome

AF:

0.108

Gnomad EAS exome

AF:

0.000544

Gnomad FIN exome

AF:

0.0420

Gnomad NFE exome

AF:

0.0541

Gnomad OTH exome

AF:

0.0681

GnomAD4 exome

AF:

0.0540

AC:

79004

AN:

1461820

Hom.:

3409

Cov.:

AF XY:

0.0528

AC XY:

38363

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.292

AC:

9784

AN:

33478

American (AMR)

AF:

0.0592

AC:

2646

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.112

AC:

2921

AN:

26136

East Asian (EAS)

AF:

0.000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0291

AC:

2510

AN:

86258

European-Finnish (FIN)

AF:

0.0426

AC:

2274

AN:

53408

Middle Eastern (MID)

AF:

0.100

AC:

577

AN:

5768

European-Non Finnish (NFE)

AF:

0.0486

AC:

54062

AN:

1111954

Other (OTH)

AF:

0.0699

AC:

4220

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

3758

7517

11275

15034

18792

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2114

4228

6342

8456

10570

<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:

0.119

AC:

18115

AN:

152042

Hom.:

1995

Cov.:

AF XY:

0.117

AC XY:

8691

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.290

AC:

12019

AN:

41408

American (AMR)

AF:

0.0933

AC:

1426

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.117

AC:

407

AN:

3470

East Asian (EAS)

AF:

0.000580

AC:

AN:

5168

South Asian (SAS)

AF:

0.0278

AC:

134

AN:

4822

European-Finnish (FIN)

AF:

0.0404

AC:

427

AN:

10578

Middle Eastern (MID)

AF:

0.136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0495

AC:

3367

AN:

68002

Other (OTH)

AF:

0.126

AC:

266

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

717

1434

2151

2868

3585

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

174

348

522

696

870

<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:

0.0801

Hom.:

2647

Bravo

AF:

0.132

TwinsUK

AF:

0.0442

AC:

164

ALSPAC

AF:

0.0459

AC:

177

ESP6500AA

AF:

0.286

AC:

1259

ESP6500EA

AF:

0.0548

AC:

471

ExAC

AF:

0.0678

AC:

8226

Asia WGS

AF:

0.0220

AC:

AN:

3478

EpiCase

AF:

0.0579

EpiControl

AF:

0.0630

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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. -

PreventionGenetics, part of Exact Sciences

Significance:Likely 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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 28, 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. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 02, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

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

0.075

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

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

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.74

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

MetaRNN

Benign

0.0038

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

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

PhyloP100

1.6

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.7

N;N;N;N;N;N;N

REVEL

Benign

0.041

Sift

Benign

0.43

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

Sift4G

Benign

0.43

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

Polyphen

0.0010

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

Vest4

0.16

MPC

0.12

ClinPred

0.011

GERP RS

4.0

PromoterAI

-0.012

Neutral

(source)

Varity_R

0.15

gMVP

0.11

Mutation Taster

=95/5

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