rs2147377

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.21904T>G(p.Phe7302Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.99 in 1,614,028 control chromosomes in the GnomAD database, including 790,225 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 (★★). Synonymous variant affecting the same amino acid position (i.e. F7302F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.99 ( 74874 hom., cov: 31)

Exomes 𝑓: 0.99 ( 715351 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 1.39

Publications

28 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=1.3821004E-6).

BP6

Variant 6-152219143-A-C is Benign according to our data. Variant chr6-152219143-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.989 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4 link	c.21904T>G	p.Phe7302Val	missense_variant	Exon 120 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.21904T>G	p.Phe7302Val	missense_variant	Exon 120 of 146	1	NM_182961.4	ENSP00000356224.5		Q8NF91-1

Frequencies

GnomAD3 genomes

AF:

0.992

AC:

150863

AN:

152120

Hom.:

74815

Cov.:

show subpopulations

Gnomad AFR

AF:

0.997

Gnomad AMI

AF:

0.953

Gnomad AMR

AF:

0.993

Gnomad ASJ

AF:

0.995

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

0.998

Gnomad FIN

AF:

0.989

Gnomad MID

AF:

0.997

Gnomad NFE

AF:

0.988

Gnomad OTH

AF:

0.991

GnomAD2 exomes

AF:

0.992

AC:

249278

AN:

251310

AF XY:

0.992

show subpopulations

Gnomad AFR exome

AF:

0.998

Gnomad AMR exome

AF:

0.994

Gnomad ASJ exome

AF:

0.994

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

0.988

Gnomad NFE exome

AF:

0.988

Gnomad OTH exome

AF:

0.991

GnomAD4 exome

AF:

0.989

AC:

1446165

AN:

1461790

Hom.:

715351

Cov.:

AF XY:

0.989

AC XY:

719528

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.998

AC:

33424

AN:

33478

American (AMR)

AF:

0.994

AC:

44460

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.994

AC:

25983

AN:

26136

East Asian (EAS)

AF:

1.00

AC:

39698

AN:

39698

South Asian (SAS)

AF:

0.998

AC:

86100

AN:

86256

European-Finnish (FIN)

AF:

0.988

AC:

52774

AN:

53414

Middle Eastern (MID)

AF:

0.996

AC:

5739

AN:

5764

European-Non Finnish (NFE)

AF:

0.988

AC:

1098223

AN:

1111928

Other (OTH)

AF:

0.990

AC:

59764

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

916

1831

2747

3662

4578

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21668

43336

65004

86672

108340

<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:

0.992

AC:

150981

AN:

152238

Hom.:

74874

Cov.:

AF XY:

0.992

AC XY:

73807

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.997

AC:

41446

AN:

41550

American (AMR)

AF:

0.993

AC:

15171

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.995

AC:

3449

AN:

3466

East Asian (EAS)

AF:

1.00

AC:

5161

AN:

5162

South Asian (SAS)

AF:

0.998

AC:

4806

AN:

4814

European-Finnish (FIN)

AF:

0.989

AC:

10494

AN:

10612

Middle Eastern (MID)

AF:

0.997

AC:

293

AN:

294

European-Non Finnish (NFE)

AF:

0.988

AC:

67200

AN:

68034

Other (OTH)

AF:

0.991

AC:

2094

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

134

201

268

335

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.990

Hom.:

219731

Bravo

AF:

0.992

TwinsUK

AF:

0.987

AC:

3658

ALSPAC

AF:

0.988

AC:

3807

ESP6500AA

AF:

0.999

AC:

4401

ESP6500EA

AF:

0.990

AC:

8515

ExAC

AF:

0.992

AC:

120475

Asia WGS

AF:

0.999

AC:

3475

AN:

3478

EpiCase

AF:

0.988

EpiControl

AF:

0.988

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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. -

Sep 26, 2016

Eurofins Ntd Llc (ga)

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

- -

Jan 25, 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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Benign:2

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

- -

Emery-Dreifuss muscular dystrophy 4, autosomal dominant

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 15, 2021

Genome-Nilou Lab

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

- -

Arthrogryposis multiplex congenita 3, myogenic type

Benign:1

Jul 15, 2021

Genome-Nilou Lab

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

0.036

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.65

CADD

Benign

(source)

DANN

Benign

0.21

DEOGEN2

Benign

0.078

T;.;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.87

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.044

T;T;T;T

MetaRNN

Benign

0.0000014

T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-2.3

N;.;.;.

PhyloP100

1.4

PrimateAI

Benign

0.40

PROVEAN

Benign

2.2

N;.;N;N

REVEL

Benign

0.039

Sift

Benign

1.0

T;.;T;T

Sift4G

Benign

1.0

T;T;T;T

Polyphen

0.0

B;.;.;.

Vest4

0.069

MPC

0.17

ClinPred

0.00072

GERP RS

4.0

Varity_R

0.059

gMVP

0.079

Mutation Taster

=100/0

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