rs35763277

Positions:

chr6-152211567-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_182961.4(SYNE1):c.22516A>G(p.Ser7506Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0153 in 1,613,628 control chromosomes in the GnomAD database, including 268 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 19 hom., cov: 32)

Exomes 𝑓: 0.016 ( 249 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.89

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=0.009470105).

BP6

Variant 6-152211567-T-C is Benign according to our data. Variant chr6-152211567-T-C is described in ClinVar as [Benign]. Clinvar id is 130422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152211567-T-C is described in Lovd as [Benign]. Variant chr6-152211567-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0112 (1704/152292) while in subpopulation NFE AF= 0.0161 (1096/68024). AF 95% confidence interval is 0.0153. There are 19 homozygotes in gnomad4. There are 851 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1704 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE1	NM_182961.4 linkuse as main transcript	c.22516A>G	p.Ser7506Gly	missense_variant	124/146	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.22516A>G	p.Ser7506Gly	missense_variant	124/146	1	NM_182961.4	ENSP00000356224	P1	Q8NF91-1

Frequencies

GnomAD3 genomes

AF:

0.0112

AC:

1704

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00285

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00753

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0293

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0161

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.0127

AC:

3183

AN:

250946

Hom.:

AF XY:

0.0123

AC XY:

1668

AN XY:

135612

show subpopulations

Gnomad AFR exome

AF:

0.00295

Gnomad AMR exome

AF:

0.00361

Gnomad ASJ exome

AF:

0.00695

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00284

Gnomad FIN exome

AF:

0.0276

Gnomad NFE exome

AF:

0.0192

Gnomad OTH exome

AF:

0.0132

GnomAD4 exome

AF:

0.0158

AC:

23061

AN:

1461336

Hom.:

249

Cov.:

AF XY:

0.0153

AC XY:

11092

AN XY:

726984

show subpopulations

Gnomad4 AFR exome

AF:

0.00227

Gnomad4 AMR exome

AF:

0.00389

Gnomad4 ASJ exome

AF:

0.00754

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00293

Gnomad4 FIN exome

AF:

0.0276

Gnomad4 NFE exome

AF:

0.0181

Gnomad4 OTH exome

AF:

0.0128

GnomAD4 genome

AF:

0.0112

AC:

1704

AN:

152292

Hom.:

Cov.:

AF XY:

0.0114

AC XY:

851

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00284

Gnomad4 AMR

AF:

0.00752

Gnomad4 ASJ

AF:

0.00778

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.0293

Gnomad4 NFE

AF:

0.0161

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.0131

Hom.:

Bravo

AF:

0.00978

TwinsUK

AF:

0.0135

AC:

ALSPAC

AF:

0.0205

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0171

AC:

147

ExAC

AF:

0.0137

AC:

1660

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0152

EpiControl

AF:

0.0159

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	Mar 12, 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, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 20, 2020	- -

not provided

Benign:2

Likely 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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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

0.22

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

D;.;T;T;T

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D;D;D

MetaRNN

Benign

0.0095

T;T;T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.4

M;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.9

D;.;D;D;D

REVEL

Uncertain

0.41

Sift

Benign

0.060

T;.;T;T;T

Sift4G

Uncertain

0.0040

D;D;T;D;D

Polyphen

1.0

D;.;.;.;.

Vest4

0.73

MPC

0.57

ClinPred

0.011

GERP RS

5.6

Varity_R

0.36

gMVP

0.33

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