rs4870093

Positions:

chr6-152331049-C-T

Variant summary

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

The NM_182961.4(SYNE1):c.13636G>A(p.Val4546Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,614,156 control chromosomes in the GnomAD database, including 39 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 0.0012 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 37 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.54

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=0.0048621).

BP6

Variant 6-152331049-C-T is Benign according to our data. Variant chr6-152331049-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 284688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152331049-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00134 (1960/1461876) while in subpopulation AMR AF= 0.0263 (1178/44724). AF 95% confidence interval is 0.0251. There are 37 homozygotes in gnomad4_exome. There are 914 alleles in male gnomad4_exome subpopulation. Median coverage is 83. This position pass quality control queck.

BS2

High AC in GnomAd4 at 182 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4 linkuse as main transcript	c.13636G>A	p.Val4546Ile	missense_variant	78/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10 linkuse as main transcript	c.13636G>A	p.Val4546Ile	missense_variant	78/146	1	NM_182961.4	P1	Q8NF91-1
SYNE1	ENST00000423061.6 linkuse as main transcript	c.13423G>A	p.Val4475Ile	missense_variant	77/146	1
SYNE1	ENST00000490135.6 linkuse as main transcript	n.982G>A		non_coding_transcript_exon_variant	2/11	1

Frequencies

GnomAD3 genomes

AF:

0.00119

AC:

181

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00864

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00598

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00440

AC:

1106

AN:

251408

Hom.:

AF XY:

0.00365

AC XY:

496

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0276

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00647

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00134

AC:

1960

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

914

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.0263

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0174

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.00106

GnomAD4 genome

AF:

0.00120

AC:

182

AN:

152280

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.00869

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00599

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.0221

Hom.:

2396

Bravo

AF:

0.00270

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00347

AC:

421

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

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

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	Eurofins Ntd Llc (ga)	Nov 06, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 02, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Dec 28, 2016

- -

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

0.089

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.71

DEOGEN2

Benign

0.092

T;T

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.83

T;T

MetaRNN

Benign

0.0049

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.19

N;N

REVEL

Benign

0.055

Sift

Benign

0.25

T;T

Sift4G

Benign

0.38

T;T

Polyphen

0.0060

B;.

Vest4

0.16

MVP

0.31

MPC

0.11

ClinPred

0.016

GERP RS

5.2

Varity_R

0.068

gMVP

0.084

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