rs2306914

Positions:

chr6-152318975-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_182961.4(SYNE1):c.16277C>T(p.Thr5426Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0331 in 1,614,120 control chromosomes in the GnomAD database, including 1,416 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 124 hom., cov: 33)

Exomes 𝑓: 0.034 ( 1292 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.908

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 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=0.0011658967).

BP6

Variant 6-152318975-G-A is Benign according to our data. Variant chr6-152318975-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 130410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152318975-G-A is described in Lovd as [Benign]. Variant chr6-152318975-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE1	NM_182961.4 linkuse as main transcript	c.16277C>T	p.Thr5426Met	missense_variant	85/146	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.16277C>T	p.Thr5426Met	missense_variant	85/146	1	NM_182961.4	ENSP00000356224	P1	Q8NF91-1

Frequencies

GnomAD3 genomes

AF:

0.0282

AC:

4291

AN:

152164

Hom.:

124

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00649

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0291

Gnomad ASJ

AF:

0.0182

Gnomad EAS

AF:

0.151

Gnomad SAS

AF:

0.0325

Gnomad FIN

AF:

0.0375

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0309

Gnomad OTH

AF:

0.0282

GnomAD3 exomes

AF:

0.0410

AC:

10296

AN:

251368

Hom.:

416

AF XY:

0.0396

AC XY:

5379

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.00535

Gnomad AMR exome

AF:

0.0493

Gnomad ASJ exome

AF:

0.0156

Gnomad EAS exome

AF:

0.165

Gnomad SAS exome

AF:

0.0281

Gnomad FIN exome

AF:

0.0401

Gnomad NFE exome

AF:

0.0295

Gnomad OTH exome

AF:

0.0362

GnomAD4 exome

AF:

0.0336

AC:

49184

AN:

1461838

Hom.:

1292

Cov.:

AF XY:

0.0332

AC XY:

24113

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.00496

Gnomad4 AMR exome

AF:

0.0489

Gnomad4 ASJ exome

AF:

0.0150

Gnomad4 EAS exome

AF:

0.155

Gnomad4 SAS exome

AF:

0.0254

Gnomad4 FIN exome

AF:

0.0406

Gnomad4 NFE exome

AF:

0.0303

Gnomad4 OTH exome

AF:

0.0341

GnomAD4 genome

AF:

0.0282

AC:

4287

AN:

152282

Hom.:

124

Cov.:

AF XY:

0.0290

AC XY:

2163

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00648

Gnomad4 AMR

AF:

0.0291

Gnomad4 ASJ

AF:

0.0182

Gnomad4 EAS

AF:

0.151

Gnomad4 SAS

AF:

0.0323

Gnomad4 FIN

AF:

0.0375

Gnomad4 NFE

AF:

0.0309

Gnomad4 OTH

AF:

0.0284

Alfa

AF:

0.0293

Hom.:

174

Bravo

AF:

0.0282

TwinsUK

AF:

0.0297

AC:

110

ALSPAC

AF:

0.0317

AC:

122

ESP6500AA

AF:

0.00590

AC:

ESP6500EA

AF:

0.0272

AC:

234

ExAC

AF:

0.0393

AC:

4768

Asia WGS

AF:

0.0770

AC:

267

AN:

3478

EpiCase

AF:

0.0281

EpiControl

AF:

0.0261

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 28, 2016	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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Autosomal recessive ataxia, Beauce type

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Emery-Dreifuss muscular dystrophy 4, autosomal dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.71

CADD

Benign

DANN

Benign

0.61

DEOGEN2

Benign

0.070

T;.;T;.

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.71

T;T;T;T

MetaRNN

Benign

0.0012

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.5

N;.;.;.

MutationTaster

Benign

1.0

P;P;P;P;P

PrimateAI

Benign

0.24

PROVEAN

Benign

0.28

N;.;N;.

REVEL

Benign

0.053

Sift

Benign

0.19

T;.;T;.

Sift4G

Benign

0.57

T;T;T;T

Polyphen

0.0010

B;.;.;.

Vest4

0.062

MPC

0.14

ClinPred

0.0087

GERP RS

0.29

Varity_R

0.023

gMVP

0.082

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