rs75989452

Positions:

chr6-152409138-T-C

Variant summary

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

The NM_182961.4(SYNE1):c.6470A>G(p.Lys2157Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00462 in 1,614,154 control chromosomes in the GnomAD database, including 220 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 123 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 97 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.75

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 where missense usually causes diseases, SYNE1

BP4

Computational evidence support a benign effect (MetaRNN=0.0024335384).

BP6

Variant 6-152409138-T-C is Benign according to our data. Variant chr6-152409138-T-C is described in ClinVar as [Benign]. Clinvar id is 130448.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152409138-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0759 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4 linkuse as main transcript	c.6470A>G	p.Lys2157Arg	missense_variant	44/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10 linkuse as main transcript	c.6470A>G	p.Lys2157Arg	missense_variant	44/146	1	NM_182961.4	P1	Q8NF91-1
SYNE1	ENST00000423061.6 linkuse as main transcript	c.6491A>G	p.Lys2164Arg	missense_variant	44/146	1
SYNE1	ENST00000461872.6 linkuse as main transcript	n.6688A>G		non_coding_transcript_exon_variant	42/55	1
SYNE1	ENST00000535081.1 linkuse as main transcript	n.167A>G		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes

AF:

0.0230

AC:

3493

AN:

152194

Hom.:

122

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0779

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.0143

GnomAD3 exomes

AF:

0.00597

AC:

1501

AN:

251412

Hom.:

AF XY:

0.00444

AC XY:

604

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.0767

Gnomad AMR exome

AF:

0.00445

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000633

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00270

AC:

3950

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00242

AC XY:

1759

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0800

Gnomad4 AMR exome

AF:

0.00555

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000530

Gnomad4 OTH exome

AF:

0.00637

GnomAD4 genome

AF:

0.0231

AC:

3513

AN:

152312

Hom.:

123

Cov.:

AF XY:

0.0222

AC XY:

1654

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.0782

Gnomad4 AMR

AF:

0.0117

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000735

Gnomad4 OTH

AF:

0.0142

Alfa

AF:

0.00713

Hom.:

Bravo

AF:

0.0268

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.0722

AC:

318

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00704

AC:

855

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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	Athena Diagnostics	Feb 13, 2020	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 21, 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

Invitae

Jan 26, 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

0.080

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;.;T

Eigen

Benign

0.0062

Eigen_PC

Benign

0.015

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.76

T;T;T

MetaRNN

Benign

0.0024

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

2.0

M;.;.

MutationTaster

Benign

0.67

N;N;N;N;N

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.3

N;N;N

REVEL

Benign

0.085

Sift

Benign

0.034

D;D;D

Sift4G

Benign

0.11

T;T;T

Polyphen

0.99

D;.;.

Vest4

0.32

MVP

0.61

MPC

0.11

ClinPred

0.013

GERP RS

4.4

Varity_R

0.065

gMVP

0.052

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