rs117501809

Positions:

chr6-152336927-C-G

Variant summary

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

The NM_182961.4(SYNE1):c.12442G>C(p.Asp4148His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0306 in 1,614,180 control chromosomes in the GnomAD database, including 913 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. D4148D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.022 ( 45 hom., cov: 32)

Exomes 𝑓: 0.031 ( 868 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.90

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=0.0064047575).

BP6

Variant 6-152336927-C-G is Benign according to our data. Variant chr6-152336927-C-G is described in ClinVar as [Benign]. Clinvar id is 130401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152336927-C-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0219 (3339/152338) while in subpopulation NFE AF= 0.0344 (2343/68036). AF 95% confidence interval is 0.0333. There are 45 homozygotes in gnomad4. There are 1570 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3339 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4 linkuse as main transcript	c.12442G>C	p.Asp4148His	missense_variant	76/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10 linkuse as main transcript	c.12442G>C	p.Asp4148His	missense_variant	76/146	1	NM_182961.4	P1	Q8NF91-1
SYNE1	ENST00000423061.6 linkuse as main transcript	c.12229G>C	p.Asp4077His	missense_variant	75/146	1
SYNE1	ENST00000471834.1 linkuse as main transcript	n.5580G>C		non_coding_transcript_exon_variant	19/19	1

Frequencies

GnomAD3 genomes

AF:

0.0219

AC:

3339

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00511

Gnomad AMI

AF:

0.0603

Gnomad AMR

AF:

0.0117

Gnomad ASJ

AF:

0.00980

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0275

Gnomad FIN

AF:

0.0322

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0344

Gnomad OTH

AF:

0.0163

GnomAD3 exomes

AF:

0.0253

AC:

6362

AN:

251382

Hom.:

110

AF XY:

0.0267

AC XY:

3631

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.00597

Gnomad AMR exome

AF:

0.00966

Gnomad ASJ exome

AF:

0.00893

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0313

Gnomad FIN exome

AF:

0.0314

Gnomad NFE exome

AF:

0.0355

Gnomad OTH exome

AF:

0.0257

GnomAD4 exome

AF:

0.0315

AC:

46007

AN:

1461842

Hom.:

868

Cov.:

AF XY:

0.0315

AC XY:

22885

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00493

Gnomad4 AMR exome

AF:

0.0101

Gnomad4 ASJ exome

AF:

0.00899

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0319

Gnomad4 FIN exome

AF:

0.0308

Gnomad4 NFE exome

AF:

0.0350

Gnomad4 OTH exome

AF:

0.0273

GnomAD4 genome

AF:

0.0219

AC:

3339

AN:

152338

Hom.:

Cov.:

AF XY:

0.0211

AC XY:

1570

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00510

Gnomad4 AMR

AF:

0.0116

Gnomad4 ASJ

AF:

0.00980

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0280

Gnomad4 FIN

AF:

0.0322

Gnomad4 NFE

AF:

0.0344

Gnomad4 OTH

AF:

0.0161

Alfa

AF:

0.0287

Hom.:

Bravo

AF:

0.0192

TwinsUK

AF:

0.0345

AC:

128

ALSPAC

AF:

0.0324

AC:

125

ESP6500AA

AF:

0.00681

AC:

ESP6500EA

AF:

0.0326

AC:

280

ExAC

AF:

0.0272

AC:

3298

Asia WGS

AF:

0.00924

AC:

AN:

3478

EpiCase

AF:

0.0343

EpiControl

AF:

0.0319

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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	GeneDx	Mar 11, 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	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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 07, 2019

- -

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

Pathogenic

0.64

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.58

D;.;T

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

D;D;D

MetaRNN

Benign

0.0064

T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.1

M;.;.

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-2.8

D;.;D

REVEL

Uncertain

0.32

Sift

Uncertain

0.0020

D;.;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.68

MPC

0.66

ClinPred

0.011

GERP RS

5.5

Varity_R

0.58

gMVP

0.46

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