rs35591210

Positions:

chr6-152132156-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.26060C>T(p.Thr8687Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.068 in 1,613,876 control chromosomes in the GnomAD database, including 4,295 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 0.050 ( 240 hom., cov: 32)

Exomes 𝑓: 0.070 ( 4055 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.82

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=0.0016930401).

BP6

Variant 6-152132156-G-A is Benign according to our data. Variant chr6-152132156-G-A is described in ClinVar as [Benign]. Clinvar id is 130433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152132156-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0764 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.26060C>T	p.Thr8687Ile	missense_variant	144/146	ENST00000367255.10	NP_892006.3
SYNE1	NM_001347702.2 linkuse as main transcript	c.2594C>T	p.Thr865Ile	missense_variant	16/18	ENST00000354674.5	NP_001334631.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10 linkuse as main transcript	c.26060C>T	p.Thr8687Ile	missense_variant	144/146	1	NM_182961.4	ENSP00000356224	P1	Q8NF91-1
SYNE1	ENST00000354674.5 linkuse as main transcript	c.2594C>T	p.Thr865Ile	missense_variant	16/18	5	NM_001347702.2	ENSP00000346701

Frequencies

GnomAD3 genomes

AF:

0.0498

AC:

7575

AN:

152152

Hom.:

240

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0133

Gnomad AMI

AF:

0.0570

Gnomad AMR

AF:

0.0430

Gnomad ASJ

AF:

0.0481

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0232

Gnomad FIN

AF:

0.0568

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0782

Gnomad OTH

AF:

0.0498

GnomAD3 exomes

AF:

0.0510

AC:

12818

AN:

251494

Hom.:

416

AF XY:

0.0518

AC XY:

7034

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.0126

Gnomad AMR exome

AF:

0.0341

Gnomad ASJ exome

AF:

0.0449

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0208

Gnomad FIN exome

AF:

0.0593

Gnomad NFE exome

AF:

0.0769

Gnomad OTH exome

AF:

0.0497

GnomAD4 exome

AF:

0.0699

AC:

102202

AN:

1461606

Hom.:

4055

Cov.:

AF XY:

0.0686

AC XY:

49910

AN XY:

727130

show subpopulations

Gnomad4 AFR exome

AF:

0.0109

Gnomad4 AMR exome

AF:

0.0339

Gnomad4 ASJ exome

AF:

0.0489

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0222

Gnomad4 FIN exome

AF:

0.0593

Gnomad4 NFE exome

AF:

0.0809

Gnomad4 OTH exome

AF:

0.0634

GnomAD4 genome

AF:

0.0497

AC:

7570

AN:

152270

Hom.:

240

Cov.:

AF XY:

0.0477

AC XY:

3555

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0133

Gnomad4 AMR

AF:

0.0429

Gnomad4 ASJ

AF:

0.0481

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0232

Gnomad4 FIN

AF:

0.0568

Gnomad4 NFE

AF:

0.0782

Gnomad4 OTH

AF:

0.0488

Alfa

AF:

0.0694

Hom.:

672

Bravo

AF:

0.0478

TwinsUK

AF:

0.0801

AC:

297

ALSPAC

AF:

0.0823

AC:

317

ESP6500AA

AF:

0.0152

AC:

ESP6500EA

AF:

0.0745

AC:

641

ExAC

AF:

0.0513

AC:

6234

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.0793

EpiControl

AF:

0.0737

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 23, 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	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Jan 31, 2024

- -

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

0.093

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

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

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.14

LIST_S2

Uncertain

0.86

D;D;D;D;D;D;D

MetaRNN

Benign

0.0017

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

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

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.4

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

REVEL

Benign

0.073

Sift

Benign

0.061

T;.;D;T;D;D;D

Sift4G

Uncertain

0.010

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

Polyphen

0.0040

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

Vest4

0.26

MPC

0.14

ClinPred

0.0074

GERP RS

2.6

Varity_R

0.029

gMVP

0.22

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