chr6-152390293-C-T

Position:

chr6-152390293-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_182961.4(SYNE1):c.8164G>A(p.Val2722Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00741 in 1,613,912 control chromosomes in the GnomAD database, including 60 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 (★★).

Frequency

Genomes: 𝑓 0.0067 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0075 ( 58 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.705

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:

SYNE1 (HGNC:):

SYNE1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 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=0.0038227737).

BP6

Variant 6-152390293-C-T is Benign according to our data. Variant chr6-152390293-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 197955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152390293-C-T is described in Lovd as [Benign]. Variant chr6-152390293-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 1018 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE1	NM_182961.4 linkuse as main transcript	c.8164G>A	p.Val2722Ile	missense_variant	53/146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SYNE1	ENST00000367255.10 linkuse as main transcript	c.8164G>A	p.Val2722Ile	missense_variant	53/146	1	NM_182961.4	ENSP00000356224.5	Q8NF91-1
SYNE1	ENST00000423061.6 linkuse as main transcript	c.8185G>A	p.Val2729Ile	missense_variant	53/146	1		ENSP00000396024.1	A0A0C4DG40
SYNE1	ENST00000461872.6 linkuse as main transcript	n.8382G>A		non_coding_transcript_exon_variant	51/55	1

Frequencies

GnomAD3 genomes

AF:

0.00669

AC:

1018

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00186

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.00400

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.0116

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00969

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00607

AC:

1524

AN:

251248

Hom.:

AF XY:

0.00627

AC XY:

851

AN XY:

135788

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00159

Gnomad ASJ exome

AF:

0.0103

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00366

Gnomad FIN exome

AF:

0.0111

Gnomad NFE exome

AF:

0.00847

Gnomad OTH exome

AF:

0.00457

GnomAD4 exome

AF:

0.00749

AC:

10946

AN:

1461708

Hom.:

Cov.:

AF XY:

0.00756

AC XY:

5500

AN XY:

727146

show subpopulations

Gnomad4 AFR exome

AF:

0.00122

Gnomad4 AMR exome

AF:

0.00174

Gnomad4 ASJ exome

AF:

0.0111

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.00393

Gnomad4 FIN exome

AF:

0.0104

Gnomad4 NFE exome

AF:

0.00829

Gnomad4 OTH exome

AF:

0.00643

GnomAD4 genome

AF:

0.00669

AC:

1018

AN:

152204

Hom.:

Cov.:

AF XY:

0.00642

AC XY:

478

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00185

Gnomad4 AMR

AF:

0.00399

Gnomad4 ASJ

AF:

0.0127

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.0116

Gnomad4 NFE

AF:

0.00969

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00842

Hom.:

Bravo

AF:

0.00599

TwinsUK

AF:

0.00917

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.00204

AC:

ESP6500EA

AF:

0.00977

AC:

ExAC

AF:

0.00632

AC:

767

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00807

EpiControl

AF:

0.00782

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

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	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 09, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 30, 2017	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	Jul 12, 2017	- -

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 15, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SYNE1: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 29, 2024

- -

Autosomal recessive ataxia, Beauce type

Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

SYNE1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 23, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Emery-Dreifuss muscular dystrophy 4, autosomal dominant

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.0080

DANN

Benign

0.69

DEOGEN2

Benign

0.12

T;.;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.27

T;T;T

MetaRNN

Benign

0.0038

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

L;.;.

PrimateAI

Benign

0.23

PROVEAN

Benign

0.090

N;.;N

REVEL

Benign

0.039

Sift

Benign

0.53

T;.;T

Sift4G

Benign

0.14

T;T;T

Polyphen

0.0010

B;.;.

Vest4

0.12

MVP

0.085

MPC

0.11

ClinPred

0.0026

GERP RS

-12

Varity_R

0.018

gMVP

0.024

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