6-152369124-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_182961.4(SYNE1):c.9655G>A(p.Val3219Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000211 in 1,613,214 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 3.82

Publications

2 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009579062).

BP6

Variant 6-152369124-C-T is Benign according to our data. Variant chr6-152369124-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 290182.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4 link	c.9655G>A	p.Val3219Ile	missense_variant	Exon 61 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.9655G>A	p.Val3219Ile	missense_variant	Exon 61 of 146	1	NM_182961.4	ENSP00000356224.5

Frequencies

GnomAD3 genomes

AF:

0.00120

AC:

183

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00415

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000244

AC:

AN:

250120

AF XY:

0.000155

show subpopulations

Gnomad AFR exome

AF:

0.00345

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000108

AC:

158

AN:

1460918

Hom.:

Cov.:

AF XY:

0.0000826

AC XY:

AN XY:

726818

show subpopulations

African (AFR)

AF:

0.00388

AC:

130

AN:

33474

American (AMR)

AF:

0.000179

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52812

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5490

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111990

Other (OTH)

AF:

0.000298

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00120

AC:

183

AN:

152296

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00414

AC:

172

AN:

41550

American (AMR)

AF:

0.000457

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000454

Hom.:

Bravo

AF:

0.00141

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000296

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Nov 13, 2018

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A variant of uncertain significance has been identified in the SYNE1 gene. The V3226I variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The V3226I variant is observed in 34/10238 (0.3%) alleles from individuals of African background, in the ExAC dataset (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The V3226I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Valine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Jun 19, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SYNE1: BS1 -

not specified

Benign:1

Oct 29, 2024

Athena Diagnostics

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

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SYNE1-related disorder

Benign:1

Apr 05, 2019

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.091

T;.;T;T

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Benign

0.0084

MetaRNN

Benign

0.0096

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.;.;.

PhyloP100

3.8

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.34

N;.;N;.

REVEL

Benign

0.069

Sift

Uncertain

0.018

D;.;D;.

Sift4G

Benign

0.13

T;T;T;T

Polyphen

0.68

P;.;.;.

Vest4

0.46

MVP

0.37

MPC

0.20

ClinPred

0.036

GERP RS

5.7

Varity_R

0.14

gMVP

0.060

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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