chr6-152399697-T-C

Position:

chr6-152399697-T-C

Variant summary

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

The NM_182961.4(SYNE1):c.7156A>G(p.Ile2386Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000904 in 1,614,172 control chromosomes in the GnomAD database, including 3 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2386L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00097 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00090 ( 1 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 2.49

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:

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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=0.0063762665).

BP6

Variant 6-152399697-T-C is Benign according to our data. Variant chr6-152399697-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281692.We mark this variant Likely_benign, oryginal submissions are: {Benign=5, Uncertain_significance=1, Likely_benign=1}.

BS2

High AC in GnomAd4 at 147 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE1	NM_182961.4 linkuse as main transcript	c.7156A>G	p.Ile2386Val	missense_variant	48/146	ENST00000367255.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE1	ENST00000367255.10 linkuse as main transcript	c.7156A>G	p.Ile2386Val	missense_variant	48/146	1	NM_182961.4	P1	Q8NF91-1
SYNE1	ENST00000423061.6 linkuse as main transcript	c.7177A>G	p.Ile2393Val	missense_variant	48/146	1
SYNE1	ENST00000461872.6 linkuse as main transcript	n.7374A>G		non_coding_transcript_exon_variant	46/55	1

Frequencies

GnomAD3 genomes

AF:

0.000966

AC:

147

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00109

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000895

AC:

225

AN:

251280

Hom.:

AF XY:

0.000854

AC XY:

116

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.0127

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000651

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000898

AC:

1313

AN:

1461860

Hom.:

Cov.:

AF XY:

0.000866

AC XY:

630

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.0111

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000836

Gnomad4 OTH exome

AF:

0.00121

GnomAD4 genome

AF:

0.000965

AC:

147

AN:

152312

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.0153

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.00109

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00122

Hom.:

Bravo

AF:

0.000926

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000840

AC:

102

EpiCase

AF:

0.00115

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 22, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2020	In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	SYNE1: BP4, BS1 -

Autosomal recessive ataxia, Beauce type

Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 16, 2016

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 11, 2024

- -

Emery-Dreifuss muscular dystrophy 4, autosomal dominant

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.66

CADD

Benign

DANN

Benign

0.57

DEOGEN2

Benign

0.085

T;.;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.71

T;T;T

M_CAP

Benign

0.0093

MetaRNN

Benign

0.0064

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;.;.

MutationTaster

Benign

0.98

D;D;D;D;D

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.17

N;.;N

REVEL

Benign

0.044

Sift

Benign

1.0

T;.;T

Sift4G

Benign

0.34

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.24

MVP

0.26

MPC

0.11

ClinPred

0.029

GERP RS

3.7

Varity_R

0.035

gMVP

0.055

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