NM_182961.4:c.6521C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_182961.4(SYNE1):c.6521C>T(p.Thr2174Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,614,044 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T2174T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0011 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 3 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:6

Conservation

PhyloP100: 1.18

Publications

6 publications found

Variant links:

COSMIC-nc: COSV55042930

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009655803).

BP6

Variant 6-152409087-G-A is Benign according to our data. Variant chr6-152409087-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 283439.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4 link	c.6521C>T	p.Thr2174Ile	missense_variant	Exon 44 of 146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SYNE1	ENST00000367255.10 link	c.6521C>T	p.Thr2174Ile	missense_variant	Exon 44 of 146	1	NM_182961.4	ENSP00000356224.5
SYNE1	ENST00000423061.6 link	c.6542C>T	p.Thr2181Ile	missense_variant	Exon 44 of 146	1		ENSP00000396024.1
SYNE1	ENST00000461872.6 link	n.6739C>T		non_coding_transcript_exon_variant	Exon 42 of 55	1
SYNE1	ENST00000535081.1 link	n.218C>T		non_coding_transcript_exon_variant	Exon 1 of 4	2

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

174

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00159

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00126

AC:

318

AN:

251420

AF XY:

0.00120

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00197

Gnomad ASJ exome

AF:

0.00417

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00162

Gnomad NFE exome

AF:

0.00134

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00152

AC:

2227

AN:

1461818

Hom.:

Cov.:

AF XY:

0.00147

AC XY:

1072

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33480

American (AMR)

AF:

0.00210

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00421

AC:

110

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00198

AC:

106

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00161

AC:

1787

AN:

1111970

Other (OTH)

AF:

0.00200

AC:

121

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

103

206

308

411

514

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

216

288

360

<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:

0.00114

AC:

174

AN:

152226

Hom.:

Cov.:

AF XY:

0.000887

AC XY:

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41530

American (AMR)

AF:

0.00164

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00159

AC:

108

AN:

68016

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00142

Hom.:

Bravo

AF:

0.00139

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00114

AC:

139

EpiCase

AF:

0.00120

EpiControl

AF:

0.00136

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Jul 05, 2025

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Aug 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 19, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive ataxia, Beauce type

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Benign:1

Jan 08, 2017

Eurofins Ntd Llc (ga)

Significance:Likely 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

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SYNE1-related disorder

Benign:1

Feb 19, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.071

T;.;T

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.80

T;T;T

M_CAP

Benign

0.0069

MetaRNN

Benign

0.0097

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.7

M;.;.

PhyloP100

1.2

PrimateAI

Benign

0.36

PROVEAN

Benign

0.46

N;.;N

REVEL

Benign

0.086

Sift

Benign

1.0

T;.;T

Sift4G

Benign

0.79

T;T;T

Polyphen

0.0010

B;.;.

Vest4

0.35

MVP

0.43

MPC

0.14

ClinPred

0.046

GERP RS

4.7

Varity_R

0.095

gMVP

0.12

Mutation Taster

=76/24

polymorphism

(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