6-152148298-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_182961.4(SYNE1):c.24723C>G(p.His8241Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00055 in 1,613,898 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. H8241H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00047 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00056 ( 1 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: -1.19

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 -8 ACMG points.

PP2

Missense variant where missense usually causes diseases, SYNE1

BP4

Computational evidence support a benign effect (MetaRNN=0.009497613).

BP6

Variant 6-152148298-G-C is Benign according to our data. Variant chr6-152148298-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194306.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}.

BS2

High AC in GnomAd at 71 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4 linkuse as main transcript	c.24723C>G	p.His8241Gln	missense_variant	137/146	ENST00000367255.10
SYNE1	NM_001347702.2 linkuse as main transcript	c.1188C>G	p.His396Gln	missense_variant	8/18	ENST00000354674.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10 linkuse as main transcript	c.24723C>G	p.His8241Gln	missense_variant	137/146	1	NM_182961.4	P1	Q8NF91-1
SYNE1	ENST00000354674.5 linkuse as main transcript	c.1188C>G	p.His396Gln	missense_variant	8/18	5	NM_001347702.2

Frequencies

GnomAD3 genomes

AF:

0.000467

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000941

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000583

AC:

146

AN:

250554

Hom.:

AF XY:

0.000598

AC XY:

AN XY:

135382

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00125

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000559

AC:

817

AN:

1461616

Hom.:

Cov.:

AF XY:

0.000530

AC XY:

385

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.000707

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000466

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000941

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000795

Hom.:

Bravo

AF:

0.000355

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000601

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 31, 2017	The p.His8170Gln variant (rs141586001) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with a population frequency of 0.1 percent in the European Non-Finnish population (identified on 145 out of 125,962 chromosomes), and has been reported to the ClinVar database with conflicting interpretations. The histidine at position 8170 is weakly conserved and computational analyses of the p.His8170Gln variant on protein structure and function indicate a neutral effect (SIFT: tolerated, MutationTaster: polymorphism, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.His8170Gln variant with certainty. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 07, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2020	- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 19, 2022

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 8170 of the SYNE1 protein (p.His8170Gln). This variant is present in population databases (rs141586001, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SYNE1-related conditions. ClinVar contains an entry for this variant (Variation ID: 194306). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

SYNE1-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 14, 2023

The SYNE1 c.24510C>G variant is predicted to result in the amino acid substitution p.His8170Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including one homozygous individual (http://gnomad.broadinstitute.org/variant/6-152469433-G-C). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 23, 2021

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Intellectual disability

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.69

Cadd

Benign

0.0050

Dann

Benign

0.61

DEOGEN2

Benign

0.27

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

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.63

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

M_CAP

Benign

0.0027

MetaRNN

Benign

0.0095

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;.;.;.;.;.;.

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.25

PROVEAN

Benign

-1.5

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

REVEL

Benign

0.017

Sift

Benign

0.36

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

Sift4G

Benign

0.57

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

Polyphen

0.0010

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

Vest4

0.080

MutPred

0.25

Loss of catalytic residue at H8241 (P = 0.199);.;.;.;.;.;.;

MVP

0.27

MPC

0.13

ClinPred

0.061

GERP RS

-11

Varity_R

0.026

gMVP

0.24

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