6-152391305-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_182961.4(SYNE1):c.7976C>A(p.Thr2659Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,614,040 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0025 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0035 ( 14 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 3.18

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00968653).

BP6

Variant 6-152391305-G-T is Benign according to our data. Variant chr6-152391305-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197940.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=2, Uncertain_significance=1}. Variant chr6-152391305-G-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 377 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4 link	c.7976C>A	p.Thr2659Asn	missense_variant	Exon 52 of 146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SYNE1	ENST00000367255.10 link	c.7976C>A	p.Thr2659Asn	missense_variant	Exon 52 of 146	1	NM_182961.4	ENSP00000356224.5	Q8NF91-1
SYNE1	ENST00000423061.6 link	c.7997C>A	p.Thr2666Asn	missense_variant	Exon 52 of 146	1		ENSP00000396024.1	A0A0C4DG40
SYNE1	ENST00000461872.6 link	n.8194C>A		non_coding_transcript_exon_variant	Exon 50 of 55	1

Frequencies

GnomAD3 genomes

AF:

0.00247

AC:

376

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000773

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00420

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00229

AC:

574

AN:

250794

Hom.:

AF XY:

0.00247

AC XY:

335

AN XY:

135586

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00194

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00147

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.00385

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00346

AC:

5051

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00334

AC XY:

2429

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.00228

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00167

Gnomad4 FIN exome

AF:

0.000487

Gnomad4 NFE exome

AF:

0.00416

Gnomad4 OTH exome

AF:

0.00210

GnomAD4 genome

AF:

0.00248

AC:

377

AN:

152198

Hom.:

Cov.:

AF XY:

0.00243

AC XY:

181

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.000770

Gnomad4 AMR

AF:

0.00321

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00421

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00350

Hom.:

Bravo

AF:

0.00269

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.00239

AC:

290

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00387

EpiControl

AF:

0.00379

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 25, 2019

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 28, 2022

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SYNE1: BP4, BS2 -

Inborn genetic diseases

Uncertain:1

Sep 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7997C>A (p.T2666N) alteration is located in exon 52 (coding exon 51) of the SYNE1 gene. This alteration results from a C to A substitution at nucleotide position 7997, causing the threonine (T) at amino acid position 2666 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Jun 09, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive ataxia, Beauce type

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Emery-Dreifuss muscular dystrophy 4, autosomal dominant

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

0.11

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.31

T;.;T

Eigen

Benign

-0.070

Eigen_PC

Benign

-0.040

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.90

D;T;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.0097

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;.;.

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.9

N;.;N

REVEL

Benign

0.11

Sift

Benign

0.24

T;.;T

Sift4G

Uncertain

0.024

D;D;D

Polyphen

0.41

B;.;.

Vest4

0.26

MVP

0.52

MPC

0.30

ClinPred

0.027

GERP RS

5.0

Varity_R

0.10

gMVP

0.45

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