rs17082709

Variant summary

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

The NM_182961.4(SYNE1):c.2653T>G(p.Leu885Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0592 in 1,614,058 control chromosomes in the GnomAD database, including 3,084 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 Benign (★★).

Frequency

Genomes: 𝑓 0.059 ( 309 hom., cov: 33)

Exomes 𝑓: 0.059 ( 2775 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.06

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=0.0016322136).

BP6

Variant 6-152455960-A-C is Benign according to our data. Variant chr6-152455960-A-C is described in ClinVar as [Benign]. Clinvar id is 130437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152455960-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0663 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.2653T>G	p.Leu885Val	missense_variant	23/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10 linkuse as main transcript	c.2653T>G	p.Leu885Val	missense_variant	23/146	1	NM_182961.4	P1	Q8NF91-1

Frequencies

GnomAD3 genomes

AF:

0.0588

AC:

8950

AN:

152138

Hom.:

305

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0516

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0568

Gnomad ASJ

AF:

0.105

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.0448

Gnomad FIN

AF:

0.0531

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0679

Gnomad OTH

AF:

0.0737

GnomAD3 exomes

AF:

0.0548

AC:

13784

AN:

251376

Hom.:

541

AF XY:

0.0560

AC XY:

7614

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.0544

Gnomad AMR exome

AF:

0.0351

Gnomad ASJ exome

AF:

0.109

Gnomad EAS exome

AF:

0.000924

Gnomad SAS exome

AF:

0.0455

Gnomad FIN exome

AF:

0.0568

Gnomad NFE exome

AF:

0.0666

Gnomad OTH exome

AF:

0.0610

GnomAD4 exome

AF:

0.0592

AC:

86517

AN:

1461802

Hom.:

2775

Cov.:

AF XY:

0.0591

AC XY:

42982

AN XY:

727208

show subpopulations

Gnomad4 AFR exome

AF:

0.0543

Gnomad4 AMR exome

AF:

0.0375

Gnomad4 ASJ exome

AF:

0.108

Gnomad4 EAS exome

AF:

0.000328

Gnomad4 SAS exome

AF:

0.0452

Gnomad4 FIN exome

AF:

0.0544

Gnomad4 NFE exome

AF:

0.0624

Gnomad4 OTH exome

AF:

0.0605

GnomAD4 genome

AF:

0.0589

AC:

8966

AN:

152256

Hom.:

309

Cov.:

AF XY:

0.0575

AC XY:

4283

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.0519

Gnomad4 AMR

AF:

0.0567

Gnomad4 ASJ

AF:

0.105

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.0446

Gnomad4 FIN

AF:

0.0531

Gnomad4 NFE

AF:

0.0679

Gnomad4 OTH

AF:

0.0724

Alfa

AF:

0.0638

Hom.:

580

Bravo

AF:

0.0581

TwinsUK

AF:

0.0604

AC:

224

ALSPAC

AF:

0.0584

AC:

225

ESP6500AA

AF:

0.0545

AC:

240

ESP6500EA

AF:

0.0679

AC:

584

ExAC

AF:

0.0556

AC:

6747

Asia WGS

AF:

0.0360

AC:

123

AN:

3478

EpiCase

AF:

0.0680

EpiControl

AF:

0.0680

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 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. -

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

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 18, 2018

- -

Autosomal recessive ataxia, Beauce type

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. -

Emery-Dreifuss muscular dystrophy 4, autosomal dominant

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.57

Cadd

Benign

Dann

Benign

0.94

DEOGEN2

Benign

0.21

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

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.63

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

MetaRNN

Benign

0.0016

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;.;.;L;.;L;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.67

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

REVEL

Benign

0.028

Sift

Benign

0.24

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

Sift4G

Benign

0.28

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

Polyphen

0.055

B;.;.;B;B;.;B

Vest4

0.040

MPC

0.13

ClinPred

0.0029

GERP RS

1.5

Varity_R

0.048

gMVP

0.065

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