NM_182961.4:c.14061G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_182961.4(SYNE1):c.14061G>C(p.Leu4687Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0755 in 1,613,398 control chromosomes in the GnomAD database, including 7,834 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L4687L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.073 ( 839 hom., cov: 32)

Exomes 𝑓: 0.076 ( 6995 hom. )

Consequence

SYNE1
NM_182961.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.916

Publications

11 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 6-152330624-C-G is Benign according to our data. Variant chr6-152330624-C-G is described in CliVar as Benign. Clinvar id is 130405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152330624-C-G is described in CliVar as Benign. Clinvar id is 130405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152330624-C-G is described in CliVar as Benign. Clinvar id is 130405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152330624-C-G is described in CliVar as Benign. Clinvar id is 130405.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.916 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4 link	c.14061G>C	p.Leu4687Leu	synonymous_variant	Exon 78 of 146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SYNE1	ENST00000367255.10 link	c.14061G>C	p.Leu4687Leu	synonymous_variant	Exon 78 of 146	1	NM_182961.4	ENSP00000356224.5	Q8NF91-1
SYNE1	ENST00000423061.6 link	c.13848G>C	p.Leu4616Leu	synonymous_variant	Exon 77 of 146	1		ENSP00000396024.1	A0A0C4DG40
SYNE1	ENST00000490135.6 link	n.1407G>C		non_coding_transcript_exon_variant	Exon 2 of 11	1

Frequencies

GnomAD3 genomes

AF:

0.0735

AC:

11173

AN:

152112

Hom.:

836

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0398

Gnomad AMI

AF:

0.0625

Gnomad AMR

AF:

0.0795

Gnomad ASJ

AF:

0.0401

Gnomad EAS

AF:

0.431

Gnomad SAS

AF:

0.153

Gnomad FIN

AF:

0.0679

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0622

Gnomad OTH

AF:

0.0881

GnomAD2 exomes

AF:

0.0961

AC:

23947

AN:

249198

AF XY:

0.0970

show subpopulations

Gnomad AFR exome

AF:

0.0400

Gnomad AMR exome

AF:

0.0646

Gnomad ASJ exome

AF:

0.0476

Gnomad EAS exome

AF:

0.425

Gnomad FIN exome

AF:

0.0708

Gnomad NFE exome

AF:

0.0601

Gnomad OTH exome

AF:

0.0852

GnomAD4 exome

AF:

0.0757

AC:

110627

AN:

1461168

Hom.:

6995

Cov.:

AF XY:

0.0771

AC XY:

56059

AN XY:

726914

show subpopulations

African (AFR)

AF:

0.0377

AC:

1262

AN:

33480

American (AMR)

AF:

0.0649

AC:

2900

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0461

AC:

1206

AN:

26136

East Asian (EAS)

AF:

0.411

AC:

16300

AN:

39698

South Asian (SAS)

AF:

0.131

AC:

11268

AN:

86242

European-Finnish (FIN)

AF:

0.0713

AC:

3765

AN:

52774

Middle Eastern (MID)

AF:

0.0631

AC:

364

AN:

5768

European-Non Finnish (NFE)

AF:

0.0614

AC:

68262

AN:

1111968

Other (OTH)

AF:

0.0878

AC:

5300

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

6912

13824

20736

27648

34560

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2776

5552

8328

11104

13880

<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:

0.0735

AC:

11186

AN:

152230

Hom.:

839

Cov.:

AF XY:

0.0769

AC XY:

5726

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.0399

AC:

1657

AN:

41560

American (AMR)

AF:

0.0796

AC:

1217

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0401

AC:

139

AN:

3468

East Asian (EAS)

AF:

0.431

AC:

2222

AN:

5150

South Asian (SAS)

AF:

0.153

AC:

740

AN:

4822

European-Finnish (FIN)

AF:

0.0679

AC:

720

AN:

10598

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0622

AC:

4230

AN:

68020

Other (OTH)

AF:

0.0891

AC:

188

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

490

981

1471

1962

2452

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

130

260

390

520

650

<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:

0.0614

Hom.:

120

Bravo

AF:

0.0729

Asia WGS

AF:

0.281

AC:

973

AN:

3478

EpiCase

AF:

0.0579

EpiControl

AF:

0.0616

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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. -

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 28, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive ataxia, Beauce type

Benign:1

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. -

Emery-Dreifuss muscular dystrophy 4, autosomal dominant

Benign:1

Jan 12, 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

BayesDel_noAF

Benign

-0.57

CADD

Benign

5.3

(source)

DANN

Benign

0.82

PhyloP100

0.92

Mutation Taster

=98/2

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