chr6-152430143-G-T

Position:

chr6-152430143-G-T

Variant summary

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

The NM_182961.4(SYNE1):c.4757C>A(p.Thr1586Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00443 in 1,602,944 control chromosomes in the GnomAD database, including 168 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0063 ( 20 hom., cov: 33)

Exomes 𝑓: 0.0042 ( 148 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 4.38

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 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=0.0025706887).

BP6

Variant 6-152430143-G-T is Benign according to our data. Variant chr6-152430143-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 130445.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.062 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.4757C>A	p.Thr1586Lys	missense_variant	36/146	ENST00000367255.10	NP_892006.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE1	ENST00000367255.10 linkuse as main transcript	c.4757C>A	p.Thr1586Lys	missense_variant	36/146	1	NM_182961.4	ENSP00000356224	P1	Q8NF91-1
SYNE1	ENST00000423061.6 linkuse as main transcript	c.4778C>A	p.Thr1593Lys	missense_variant	36/146	1		ENSP00000396024
SYNE1	ENST00000461872.6 linkuse as main transcript	n.4975C>A		non_coding_transcript_exon_variant	34/55	1
SYNE1	ENST00000367253.8 linkuse as main transcript	c.4757C>A	p.Thr1586Lys	missense_variant	34/36	5		ENSP00000356222		Q8NF91-6

Frequencies

GnomAD3 genomes

AF:

0.00626

AC:

952

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0316

Gnomad ASJ

AF:

0.00519

Gnomad EAS

AF:

0.0368

Gnomad SAS

AF:

0.00310

Gnomad FIN

AF:

0.0111

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000956

Gnomad OTH

AF:

0.00622

GnomAD3 exomes

AF:

0.0108

AC:

2573

AN:

238176

Hom.:

AF XY:

0.00897

AC XY:

1153

AN XY:

128510

show subpopulations

Gnomad AFR exome

AF:

0.000985

Gnomad AMR exome

AF:

0.0418

Gnomad ASJ exome

AF:

0.00526

Gnomad EAS exome

AF:

0.0351

Gnomad SAS exome

AF:

0.00294

Gnomad FIN exome

AF:

0.0110

Gnomad NFE exome

AF:

0.000904

Gnomad OTH exome

AF:

0.00767

GnomAD4 exome

AF:

0.00424

AC:

6152

AN:

1450792

Hom.:

148

Cov.:

AF XY:

0.00406

AC XY:

2931

AN XY:

721104

show subpopulations

Gnomad4 AFR exome

AF:

0.000751

Gnomad4 AMR exome

AF:

0.0415

Gnomad4 ASJ exome

AF:

0.00457

Gnomad4 EAS exome

AF:

0.0640

Gnomad4 SAS exome

AF:

0.00366

Gnomad4 FIN exome

AF:

0.0113

Gnomad4 NFE exome

AF:

0.000426

Gnomad4 OTH exome

AF:

0.00440

GnomAD4 genome

AF:

0.00627

AC:

954

AN:

152152

Hom.:

Cov.:

AF XY:

0.00759

AC XY:

565

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.00123

Gnomad4 AMR

AF:

0.0317

Gnomad4 ASJ

AF:

0.00519

Gnomad4 EAS

AF:

0.0371

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.0111

Gnomad4 NFE

AF:

0.000956

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00235

Hom.:

Bravo

AF:

0.00809

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.00844

AC:

1023

Asia WGS

AF:

0.0220

AC:

AN:

3462

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 14, 2015	- -
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	May 24, 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 12, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SYNE1: BP4, BS1, BS2 -

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 31, 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. -

Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant;C5193121:Arthrogryposis multiplex congenita 3, myogenic type

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 25, 2022

- -

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

0.20

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.20

T;.;T;.

Eigen

Benign

0.047

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

D;T;D;D

MetaRNN

Benign

0.0026

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;.;.;M

MutationTaster

Benign

0.97

D;D;D;D;D;N

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.4

N;.;N;N

REVEL

Benign

0.13

Sift

Uncertain

0.017

D;.;D;T

Sift4G

Uncertain

0.0060

D;D;D;D

Polyphen

0.049

B;.;.;B

Vest4

0.25

MPC

0.19

ClinPred

0.021

GERP RS

6.0

Varity_R

0.27

gMVP

0.14

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