rs150063353

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_182961.4(SYNE1):c.20182C>T(p.Arg6728Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,614,120 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 2.13

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 Likely_benign. Variant got -1 ACMG points.

BS2

High AC in GnomAd4 at 13 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE1	NM_182961.4 link	c.20182C>T	p.Arg6728Cys	missense_variant	Exon 109 of 146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SYNE1	ENST00000367255.10 link	c.20182C>T	p.Arg6728Cys	missense_variant	Exon 109 of 146	1	NM_182961.4	ENSP00000356224.5	Q8NF91-1
SYNE1	ENST00000423061.6 link	c.19969C>T	p.Arg6657Cys	missense_variant	Exon 108 of 146	1		ENSP00000396024.1	A0A0C4DG40
SYNE1	ENST00000367256.9 link	n.3874C>T		non_coding_transcript_exon_variant	Exon 24 of 61	1
SYNE1	ENST00000409694.6 link	n.3766C>T		non_coding_transcript_exon_variant	Exon 22 of 59	1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000835

AC:

AN:

251436

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000280

Hom.:

Bravo

AF:

0.000110

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 15, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SYNE1: PM2 -

Feb 25, 2019

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:2

Sep 04, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SYNE1 c.19969C>T (p.Arg6657Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251436 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SYNE1 causing Autosomal recessive ataxia, Beauce type (8.4e-05 vs 0.0011), allowing no conclusion about variant significance. c.19969C>T has been reported in the literature in individuals affected with spastic ataxia or developmental disorders (Coutelier_2018, Turner_2019, Kaplanis_2020, Zhou_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Autosomal recessive ataxia, Beauce type. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29482223, 33057194, 31785789, 35982159). ClinVar contains an entry for this variant (Variation ID: 440314). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain:1

May 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 6657 of the SYNE1 protein (p.Arg6657Cys). This variant is present in population databases (rs150063353, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of autosomal recessive spastic ataxia (PMID: 29482223). This variant is also known as p.R6728C. ClinVar contains an entry for this variant (Variation ID: 440314). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Uncertain

0.11

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.73

D;.;T

Eigen

Uncertain

0.27

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.67

D;D;D

MetaSVM

Benign

-0.72

MutationAssessor

Uncertain

2.8

M;.;.

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-7.5

D;.;D

REVEL

Uncertain

0.34

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.88

MVP

0.51

MPC

0.70

ClinPred

0.87

GERP RS

2.5

Varity_R

0.60

gMVP

0.56

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