rs138787771

Positions:

chr6-152180281-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_182961.4(SYNE1):c.23315G>A(p.Arg7772Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00624 in 1,613,974 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0041 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0065 ( 48 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:10

Conservation

PhyloP100: 2.55

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 links:

SYNE1 (HGNC:):

SYNE1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SYNE1. . Gene score misZ -0.29069 (greater than the threshold 3.09). Trascript score misZ 3.2909 (greater than threshold 3.09). GenCC has associacion of gene with autosomal recessive ataxia, Beauce type, autosomal recessive myogenic arthrogryposis multiplex congenita, Emery-Dreifuss muscular dystrophy 4, autosomal dominant, arthrogryposis multiplex congenita 3, myogenic type, autosomal dominant Emery-Dreifuss muscular dystrophy.

BP4

Computational evidence support a benign effect (MetaRNN=0.00968194).

BP6

Variant 6-152180281-C-T is Benign according to our data. Variant chr6-152180281-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 194147.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152180281-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 631 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE1	NM_182961.4 linkuse as main transcript	c.23315G>A	p.Arg7772Gln	missense_variant	129/146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10 linkuse as main transcript	c.23315G>A	p.Arg7772Gln	missense_variant	129/146	1	NM_182961.4	ENSP00000356224.5		Q8NF91-1

Frequencies

GnomAD3 genomes

AF:

0.00414

AC:

630

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.0461

Gnomad AMR

AF:

0.00216

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00692

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00351

AC:

881

AN:

250934

Hom.:

AF XY:

0.00363

AC XY:

492

AN XY:

135604

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00109

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000784

Gnomad FIN exome

AF:

0.00153

Gnomad NFE exome

AF:

0.00641

Gnomad OTH exome

AF:

0.00376

GnomAD4 exome

AF:

0.00645

AC:

9435

AN:

1461752

Hom.:

Cov.:

AF XY:

0.00623

AC XY:

4529

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.00111

Gnomad4 AMR exome

AF:

0.000984

Gnomad4 ASJ exome

AF:

0.00153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00102

Gnomad4 FIN exome

AF:

0.00157

Gnomad4 NFE exome

AF:

0.00794

Gnomad4 OTH exome

AF:

0.00503

GnomAD4 genome

AF:

0.00415

AC:

631

AN:

152222

Hom.:

Cov.:

AF XY:

0.00372

AC XY:

277

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.00149

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.000944

Gnomad4 NFE

AF:

0.00693

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00615

Hom.:

Bravo

AF:

0.00428

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.00547

AC:

ExAC

AF:

0.00371

AC:

450

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00622

EpiControl

AF:

0.00492

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SYNE1: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2020	This variant is associated with the following publications: (PMID: 31692161, 32075053) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 12, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 03, 2017	- -

not specified

Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Apr 24, 2014	Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg7701Gln (aka R7701Q, c.23102 G>A) in SYNE1 (using NM_033071.3). The variant is novel. It is a non-conservative amino acid change with a positively charged arginine being changed to a neutral, polar glutamine. The arginine at codon 7701 is not conserved across species. In silico analysis predicts a benign effect on protein structure and function (per lab report). SYNE1 encodes nesprin 1 (nuclear envelope spectrin repeat 1). Nesprin 1 and 2 are associated with the nuclear membrane and bind lamin A and emerin. These genes are highly expressed in both heart and skeletal muscle. It has been suggested that variants in SYNE1 may contribute to Emery-Dreiffus muscular dystrophy (EDMD). Using a candidate gene approach, Zang et al (2011), sequenced SYNE1 and SYNE2 (encoding nesprin 2) in 190 patients with EDMD and EDMD-like phenotypes who did not have causative variants in LMNA or EMD. This identified three patients who carried an SYNE1 missense variant that was not present in 192 control individuals. One of these patients was a compound heterozygote for a missense variant in SYNE2. Only minimal segregation analysis could be performed. The patient who was a compound heterozygote had an affected mother, who carried the SYNE2 variant and a seemingly unaffected father, who carried the SYNE1 variant. Dr. Beth McNally’s group reported on a patient with dilated cardiomyopathy requiring heart transplant who had a missense variant in SYNE1 (p.Arg374His) (Puckelwartz et al 2010). They found that mice lacking the carboxy-terminus of nesprin-1develop cardiomyopathy with conduction system disease. SYNE1 has also been linked to autosomal recessive spinocerebellar ataxia 8. Nesprin-1 is over 8700 amino acids long. p.Arg7701Gln was observed in 47 of 8600 alleles from European Americans in the NHLBI ESP, which presumably indicated 47 of 4300 individuals were heterozygous for the variant. 12 of 4406 African American alleles (likely 6 of 2203 individuals) (as of April 23rd, 2013). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 12, 2015	- -

Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Autosomal recessive ataxia, Beauce type

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

SYNE1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2019

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

0.070

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

T;.;T;T;T

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Benign

0.0091

MetaRNN

Benign

0.0097

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.0

M;.;.;.;.

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.4

N;.;D;N;D

REVEL

Benign

0.13

Sift

Uncertain

0.027

D;.;D;D;D

Sift4G

Uncertain

0.0050

D;D;D;D;D

Polyphen

0.96

P;.;.;.;.

Vest4

0.22

MVP

0.43

MPC

0.16

ClinPred

0.045

GERP RS

3.3

Varity_R

0.14

gMVP

0.28

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over