6-152337007-T-C

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.12362A>G(p.Lys4121Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.753 in 1,613,086 control chromosomes in the GnomAD database, including 460,415 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K4121S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.80 ( 49061 hom., cov: 31)

Exomes 𝑓: 0.75 ( 411354 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 1.50

Publications

38 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=1.0020265E-6).

BP6

Variant 6-152337007-T-C is Benign according to our data. Variant chr6-152337007-T-C is described in ClinVar as Benign. ClinVar VariationId is 130399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.921 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4 link	c.12362A>G	p.Lys4121Arg	missense_variant	Exon 76 of 146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SYNE1	ENST00000367255.10 link	c.12362A>G	p.Lys4121Arg	missense_variant	Exon 76 of 146	1	NM_182961.4	ENSP00000356224.5	Q8NF91-1
SYNE1	ENST00000423061.6 link	c.12149A>G	p.Lys4050Arg	missense_variant	Exon 75 of 146	1		ENSP00000396024.1	A0A0C4DG40
SYNE1	ENST00000471834.1 link	n.5500A>G		non_coding_transcript_exon_variant	Exon 19 of 19	1

Frequencies

GnomAD3 genomes

AF:

0.798

AC:

121340

AN:

152050

Hom.:

48994

Cov.:

show subpopulations

Gnomad AFR

AF:

0.929

Gnomad AMI

AF:

0.717

Gnomad AMR

AF:

0.724

Gnomad ASJ

AF:

0.686

Gnomad EAS

AF:

0.848

Gnomad SAS

AF:

0.625

Gnomad FIN

AF:

0.832

Gnomad MID

AF:

0.614

Gnomad NFE

AF:

0.747

Gnomad OTH

AF:

0.754

GnomAD2 exomes

AF:

0.749

AC:

187478

AN:

250188

AF XY:

0.740

show subpopulations

Gnomad AFR exome

AF:

0.932

Gnomad AMR exome

AF:

0.697

Gnomad ASJ exome

AF:

0.699

Gnomad EAS exome

AF:

0.855

Gnomad FIN exome

AF:

0.836

Gnomad NFE exome

AF:

0.746

Gnomad OTH exome

AF:

0.741

GnomAD4 exome

AF:

0.748

AC:

1093367

AN:

1460918

Hom.:

411354

Cov.:

AF XY:

0.744

AC XY:

540551

AN XY:

726756

show subpopulations

African (AFR)

AF:

0.933

AC:

31218

AN:

33472

American (AMR)

AF:

0.703

AC:

31367

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.701

AC:

18303

AN:

26128

East Asian (EAS)

AF:

0.860

AC:

34144

AN:

39694

South Asian (SAS)

AF:

0.623

AC:

53709

AN:

86228

European-Finnish (FIN)

AF:

0.829

AC:

43920

AN:

52992

Middle Eastern (MID)

AF:

0.617

AC:

3559

AN:

5766

European-Non Finnish (NFE)

AF:

0.749

AC:

832070

AN:

1111614

Other (OTH)

AF:

0.747

AC:

45077

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

14677

29353

44030

58706

73383

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20314

40628

60942

81256

101570

<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:

0.798

AC:

121469

AN:

152168

Hom.:

49061

Cov.:

AF XY:

0.798

AC XY:

59409

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.929

AC:

38588

AN:

41526

American (AMR)

AF:

0.725

AC:

11071

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.686

AC:

2377

AN:

3466

East Asian (EAS)

AF:

0.848

AC:

4387

AN:

5174

South Asian (SAS)

AF:

0.625

AC:

3013

AN:

4822

European-Finnish (FIN)

AF:

0.832

AC:

8814

AN:

10596

Middle Eastern (MID)

AF:

0.605

AC:

178

AN:

294

European-Non Finnish (NFE)

AF:

0.747

AC:

50792

AN:

68000

Other (OTH)

AF:

0.757

AC:

1595

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1208

2415

3623

4830

6038

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

868

1736

2604

3472

4340

<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:

0.758

Hom.:

115891

Bravo

AF:

0.798

TwinsUK

AF:

0.740

AC:

2744

ALSPAC

AF:

0.758

AC:

2920

ESP6500AA

AF:

0.922

AC:

4064

ESP6500EA

AF:

0.719

AC:

6187

ExAC

AF:

0.751

AC:

91225

Asia WGS

AF:

0.772

AC:

2687

AN:

3478

EpiCase

AF:

0.725

EpiControl

AF:

0.727

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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. -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 10, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Jan 05, 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, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Autosomal recessive ataxia, Beauce type

Benign:2

Jan 12, 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 12, 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

- -

not provided

Benign:1

Nov 02, 2018

Athena Diagnostics

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

0.057

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.089

T;.;T

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.58

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.12

T;T;T

MetaRNN

Benign

0.0000010

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.8

N;.;.

PhyloP100

1.5

PrimateAI

Benign

0.31

PROVEAN

Benign

1.1

N;.;N

REVEL

Benign

0.050

Sift

Benign

1.0

T;.;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.081

MPC

0.11

ClinPred

0.0015

GERP RS

4.5

Varity_R

0.035

gMVP

0.16

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