chr6-152350730-T-G

Position:

chr6-152350730-T-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_182961.4(SYNE1):c.11621A>C(p.Lys3874Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0262 in 1,614,084 control chromosomes in the GnomAD database, including 1,203 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 Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 99 hom., cov: 32)

Exomes 𝑓: 0.026 ( 1104 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.447

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 -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=0.0018830597).

BP6

Variant 6-152350730-T-G is Benign according to our data. Variant chr6-152350730-T-G is described in ClinVar as [Benign]. Clinvar id is 130394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152350730-T-G is described in Lovd as [Likely_benign]. Variant chr6-152350730-T-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE1	NM_182961.4 linkuse as main transcript	c.11621A>C	p.Lys3874Thr	missense_variant	71/146	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.11621A>C	p.Lys3874Thr	missense_variant	71/146	1	NM_182961.4	ENSP00000356224.5	Q8NF91-1
SYNE1	ENST00000423061.6 linkuse as main transcript	c.11576A>C	p.Lys3859Thr	missense_variant	71/146	1		ENSP00000396024.1	A0A0C4DG40
SYNE1	ENST00000471834.1 linkuse as main transcript	n.4759A>C		non_coding_transcript_exon_variant	14/19	1

Frequencies

GnomAD3 genomes

AF:

0.0248

AC:

3765

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0105

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0429

Gnomad ASJ

AF:

0.0124

Gnomad EAS

AF:

0.130

Gnomad SAS

AF:

0.0719

Gnomad FIN

AF:

0.0206

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0196

Gnomad OTH

AF:

0.0249

GnomAD3 exomes

AF:

0.0366

AC:

9203

AN:

251310

Hom.:

338

AF XY:

0.0376

AC XY:

5103

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.00941

Gnomad AMR exome

AF:

0.0410

Gnomad ASJ exome

AF:

0.0144

Gnomad EAS exome

AF:

0.127

Gnomad SAS exome

AF:

0.0752

Gnomad FIN exome

AF:

0.0225

Gnomad NFE exome

AF:

0.0190

Gnomad OTH exome

AF:

0.0311

GnomAD4 exome

AF:

0.0263

AC:

38512

AN:

1461864

Hom.:

1104

Cov.:

AF XY:

0.0276

AC XY:

20051

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.00956

Gnomad4 AMR exome

AF:

0.0406

Gnomad4 ASJ exome

AF:

0.0138

Gnomad4 EAS exome

AF:

0.160

Gnomad4 SAS exome

AF:

0.0707

Gnomad4 FIN exome

AF:

0.0215

Gnomad4 NFE exome

AF:

0.0185

Gnomad4 OTH exome

AF:

0.0287

GnomAD4 genome

AF:

0.0247

AC:

3767

AN:

152220

Hom.:

Cov.:

AF XY:

0.0260

AC XY:

1936

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0104

Gnomad4 AMR

AF:

0.0431

Gnomad4 ASJ

AF:

0.0124

Gnomad4 EAS

AF:

0.129

Gnomad4 SAS

AF:

0.0722

Gnomad4 FIN

AF:

0.0206

Gnomad4 NFE

AF:

0.0196

Gnomad4 OTH

AF:

0.0270

Alfa

AF:

0.0228

Hom.:

207

Bravo

AF:

0.0254

TwinsUK

AF:

0.0200

AC:

ALSPAC

AF:

0.0208

AC:

ESP6500AA

AF:

0.00749

AC:

ESP6500EA

AF:

0.0201

AC:

173

ExAC

AF:

0.0364

AC:

4418

Asia WGS

AF:

0.0910

AC:

315

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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	Feb 23, 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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 12, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

9.8

DANN

Benign

0.95

DEOGEN2

Benign

0.14

T;.;T

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.39

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.69

T;T;T

MetaRNN

Benign

0.0019

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;.;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.3

N;.;N

REVEL

Benign

0.016

Sift

Benign

0.10

T;.;T

Sift4G

Benign

0.10

T;T;T

Polyphen

0.050

B;.;.

Vest4

0.16

MPC

0.16

ClinPred

0.0046

GERP RS

2.3

Varity_R

0.095

gMVP

0.071

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