rs17082236

Positions:

Variant summary

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

The NM_182961.4(SYNE1):c.24502G>T(p.Ala8168Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0602 in 1,613,862 control chromosomes in the GnomAD database, including 5,404 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A8168D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.12 ( 1995 hom., cov: 32)

Exomes 𝑓: 0.054 ( 3409 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.57

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=0.0038188696).

BP6

Variant 6-152149617-C-A is Benign according to our data. Variant chr6-152149617-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 130426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152149617-C-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.286 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.24502G>T	p.Ala8168Ser	missense_variant	136/146	ENST00000367255.10
SYNE1	NM_001347702.2 linkuse as main transcript	c.967G>T	p.Ala323Ser	missense_variant	7/18	ENST00000354674.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10 linkuse as main transcript	c.24502G>T	p.Ala8168Ser	missense_variant	136/146	1	NM_182961.4	P1	Q8NF91-1
SYNE1	ENST00000354674.5 linkuse as main transcript	c.967G>T	p.Ala323Ser	missense_variant	7/18	5	NM_001347702.2

Frequencies

GnomAD3 genomes

AF:

0.119

AC:

18087

AN:

151924

Hom.:

1993

Cov.:

show subpopulations

Gnomad AFR

AF:

0.290

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0937

Gnomad ASJ

AF:

0.117

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.0278

Gnomad FIN

AF:

0.0404

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.0495

Gnomad OTH

AF:

0.127

GnomAD3 exomes

AF:

0.0646

AC:

16253

AN:

251452

Hom.:

1122

AF XY:

0.0597

AC XY:

8115

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.298

Gnomad AMR exome

AF:

0.0560

Gnomad ASJ exome

AF:

0.108

Gnomad EAS exome

AF:

0.000544

Gnomad SAS exome

AF:

0.0293

Gnomad FIN exome

AF:

0.0420

Gnomad NFE exome

AF:

0.0541

Gnomad OTH exome

AF:

0.0681

GnomAD4 exome

AF:

0.0540

AC:

79004

AN:

1461820

Hom.:

3409

Cov.:

AF XY:

0.0528

AC XY:

38363

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.292

Gnomad4 AMR exome

AF:

0.0592

Gnomad4 ASJ exome

AF:

0.112

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.0291

Gnomad4 FIN exome

AF:

0.0426

Gnomad4 NFE exome

AF:

0.0486

Gnomad4 OTH exome

AF:

0.0699

GnomAD4 genome

AF:

0.119

AC:

18115

AN:

152042

Hom.:

1995

Cov.:

AF XY:

0.117

AC XY:

8691

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.290

Gnomad4 AMR

AF:

0.0933

Gnomad4 ASJ

AF:

0.117

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.0278

Gnomad4 FIN

AF:

0.0404

Gnomad4 NFE

AF:

0.0495

Gnomad4 OTH

AF:

0.126

Alfa

AF:

0.0690

Hom.:

1229

Bravo

AF:

0.132

TwinsUK

AF:

0.0442

AC:

164

ALSPAC

AF:

0.0459

AC:

177

ESP6500AA

AF:

0.286

AC:

1259

ESP6500EA

AF:

0.0548

AC:

471

ExAC

AF:

0.0678

AC:

8226

Asia WGS

AF:

0.0220

AC:

AN:

3478

EpiCase

AF:

0.0579

EpiControl

AF:

0.0630

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

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	-	- -
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	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 02, 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

0.075

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

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

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.30

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.74

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

MetaRNN

Benign

0.0038

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

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

MutationTaster

Benign

0.99

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

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.7

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

REVEL

Benign

0.041

Sift

Benign

0.43

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

Sift4G

Benign

0.43

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

Polyphen

0.0010

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

Vest4

0.16

MPC

0.12

ClinPred

0.011

GERP RS

4.0

Varity_R

0.15

gMVP

0.11

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