rs2252755

Variant summary

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

The NM_182961.4(SYNE1):c.24968G>C(p.Gly8323Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.34 in 1,612,836 control chromosomes in the GnomAD database, including 95,907 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 10833 hom., cov: 32)

Exomes 𝑓: 0.34 ( 85074 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 3.44

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 where missense usually causes diseases, SYNE1

BP4

Computational evidence support a benign effect (MetaRNN=0.002656132).

BP6

Variant 6-152148053-C-G is Benign according to our data. Variant chr6-152148053-C-G is described in ClinVar as [Benign]. Clinvar id is 130428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152148053-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.461 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4 linkuse as main transcript	c.24968G>C	p.Gly8323Ala	missense_variant	137/146	ENST00000367255.10
SYNE1	NM_001347702.2 linkuse as main transcript	c.1433G>C	p.Gly478Ala	missense_variant	8/18	ENST00000354674.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10 linkuse as main transcript	c.24968G>C	p.Gly8323Ala	missense_variant	137/146	1	NM_182961.4	P1	Q8NF91-1
SYNE1	ENST00000354674.5 linkuse as main transcript	c.1433G>C	p.Gly478Ala	missense_variant	8/18	5	NM_001347702.2

Frequencies

GnomAD3 genomes

AF:

0.370

AC:

56203

AN:

151872

Hom.:

10817

Cov.:

show subpopulations

Gnomad AFR

AF:

0.441

Gnomad AMI

AF:

0.296

Gnomad AMR

AF:

0.470

Gnomad ASJ

AF:

0.413

Gnomad EAS

AF:

0.313

Gnomad SAS

AF:

0.407

Gnomad FIN

AF:

0.216

Gnomad MID

AF:

0.389

Gnomad NFE

AF:

0.328

Gnomad OTH

AF:

0.409

GnomAD3 exomes

AF:

0.364

AC:

90595

AN:

248750

Hom.:

17583

AF XY:

0.360

AC XY:

48490

AN XY:

134620

show subpopulations

Gnomad AFR exome

AF:

0.444

Gnomad AMR exome

AF:

0.511

Gnomad ASJ exome

AF:

0.412

Gnomad EAS exome

AF:

0.302

Gnomad SAS exome

AF:

0.420

Gnomad FIN exome

AF:

0.220

Gnomad NFE exome

AF:

0.325

Gnomad OTH exome

AF:

0.367

GnomAD4 exome

AF:

0.337

AC:

492651

AN:

1460846

Hom.:

85074

Cov.:

AF XY:

0.339

AC XY:

246259

AN XY:

726722

show subpopulations

Gnomad4 AFR exome

AF:

0.436

Gnomad4 AMR exome

AF:

0.506

Gnomad4 ASJ exome

AF:

0.415

Gnomad4 EAS exome

AF:

0.310

Gnomad4 SAS exome

AF:

0.415

Gnomad4 FIN exome

AF:

0.222

Gnomad4 NFE exome

AF:

0.325

Gnomad4 OTH exome

AF:

0.351

GnomAD4 genome

AF:

0.370

AC:

56270

AN:

151990

Hom.:

10833

Cov.:

AF XY:

0.370

AC XY:

27503

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.441

Gnomad4 AMR

AF:

0.470

Gnomad4 ASJ

AF:

0.413

Gnomad4 EAS

AF:

0.313

Gnomad4 SAS

AF:

0.407

Gnomad4 FIN

AF:

0.216

Gnomad4 NFE

AF:

0.328

Gnomad4 OTH

AF:

0.410

Alfa

AF:

0.340

Hom.:

6658

Bravo

AF:

0.393

TwinsUK

AF:

0.340

AC:

1259

ALSPAC

AF:

0.330

AC:

1271

ESP6500AA

AF:

0.444

AC:

1958

ESP6500EA

AF:

0.337

AC:

2901

ExAC

AF:

0.358

AC:

43517

Asia WGS

AF:

0.372

AC:

1292

AN:

3478

EpiCase

AF:

0.336

EpiControl

AF:

0.340

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 20, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 09, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 02, 2018	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

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

0.090

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

Cadd

Benign

Dann

Benign

0.23

DEOGEN2

Benign

0.069

T;.;.;T;T;T;T

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.060

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.72

T;T;T;T;T;T;D

MetaRNN

Benign

0.0027

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.58

N;.;.;.;.;.;.

MutationTaster

Benign

0.81

P;P;P;P;P;P;P;P

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.59

N;.;N;N;N;N;N

REVEL

Benign

0.036

Sift

Benign

1.0

T;.;T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T;T

Polyphen

0.70

P;.;.;.;.;.;.

Vest4

0.26

MPC

0.16

ClinPred

0.046

GERP RS

5.3

Varity_R

0.14

gMVP

0.32

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