NM_182961.4:c.2653T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_182961.4(SYNE1):​c.2653T>G​(p.Leu885Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0592 in 1,614,058 control chromosomes in the GnomAD database, including 3,084 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 Benign (★★).

Frequency

Genomes: 𝑓 0.059 ( 309 hom., cov: 33)
Exomes 𝑓: 0.059 ( 2775 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

1
17

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 2.06

Publications

24 publications found
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 Gene-Disease associations (from GenCC):
  • autosomal recessive ataxia, Beauce type
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
  • arthrogryposis multiplex congenita 3, myogenic type
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • Emery-Dreifuss muscular dystrophy 4, autosomal dominant
    Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina
  • autosomal dominant Emery-Dreifuss muscular dystrophy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • autosomal recessive myogenic arthrogryposis multiplex congenita
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0016322136).
BP6
Variant 6-152455960-A-C is Benign according to our data. Variant chr6-152455960-A-C is described in ClinVar as [Benign]. Clinvar id is 130437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0663 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SYNE1NM_182961.4 linkc.2653T>G p.Leu885Val missense_variant Exon 23 of 146 ENST00000367255.10 NP_892006.3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SYNE1ENST00000367255.10 linkc.2653T>G p.Leu885Val missense_variant Exon 23 of 146 1 NM_182961.4 ENSP00000356224.5 Q8NF91-1

Frequencies

GnomAD3 genomes
AF:
0.0588
AC:
8950
AN:
152138
Hom.:
305
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0516
Gnomad AMI
AF:
0.0121
Gnomad AMR
AF:
0.0568
Gnomad ASJ
AF:
0.105
Gnomad EAS
AF:
0.00173
Gnomad SAS
AF:
0.0448
Gnomad FIN
AF:
0.0531
Gnomad MID
AF:
0.0285
Gnomad NFE
AF:
0.0679
Gnomad OTH
AF:
0.0737
GnomAD2 exomes
AF:
0.0548
AC:
13784
AN:
251376
AF XY:
0.0560
show subpopulations
Gnomad AFR exome
AF:
0.0544
Gnomad AMR exome
AF:
0.0351
Gnomad ASJ exome
AF:
0.109
Gnomad EAS exome
AF:
0.000924
Gnomad FIN exome
AF:
0.0568
Gnomad NFE exome
AF:
0.0666
Gnomad OTH exome
AF:
0.0610
GnomAD4 exome
AF:
0.0592
AC:
86517
AN:
1461802
Hom.:
2775
Cov.:
31
AF XY:
0.0591
AC XY:
42982
AN XY:
727208
show subpopulations
African (AFR)
AF:
0.0543
AC:
1818
AN:
33480
American (AMR)
AF:
0.0375
AC:
1678
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.108
AC:
2825
AN:
26130
East Asian (EAS)
AF:
0.000328
AC:
13
AN:
39692
South Asian (SAS)
AF:
0.0452
AC:
3903
AN:
86256
European-Finnish (FIN)
AF:
0.0544
AC:
2905
AN:
53396
Middle Eastern (MID)
AF:
0.0648
AC:
374
AN:
5768
European-Non Finnish (NFE)
AF:
0.0624
AC:
69349
AN:
1111964
Other (OTH)
AF:
0.0605
AC:
3652
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
4593
9186
13779
18372
22965
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
2474
4948
7422
9896
12370
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0589
AC:
8966
AN:
152256
Hom.:
309
Cov.:
33
AF XY:
0.0575
AC XY:
4283
AN XY:
74450
show subpopulations
African (AFR)
AF:
0.0519
AC:
2156
AN:
41540
American (AMR)
AF:
0.0567
AC:
867
AN:
15292
Ashkenazi Jewish (ASJ)
AF:
0.105
AC:
363
AN:
3470
East Asian (EAS)
AF:
0.00174
AC:
9
AN:
5186
South Asian (SAS)
AF:
0.0446
AC:
215
AN:
4816
European-Finnish (FIN)
AF:
0.0531
AC:
564
AN:
10620
Middle Eastern (MID)
AF:
0.0306
AC:
9
AN:
294
European-Non Finnish (NFE)
AF:
0.0679
AC:
4619
AN:
68014
Other (OTH)
AF:
0.0724
AC:
153
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.501
Heterozygous variant carriers
0
436
871
1307
1742
2178
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
100
200
300
400
500
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0628
Hom.:
772
Bravo
AF:
0.0581
TwinsUK
AF:
0.0604
AC:
224
ALSPAC
AF:
0.0584
AC:
225
ESP6500AA
AF:
0.0545
AC:
240
ESP6500EA
AF:
0.0679
AC:
584
ExAC
AF:
0.0556
AC:
6747
Asia WGS
AF:
0.0360
AC:
123
AN:
3478
EpiCase
AF:
0.0680
EpiControl
AF:
0.0680

ClinVar

Significance: Benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Genetic Services Laboratory, University of Chicago
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

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. -

Jan 30, 2016
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Benign
Review Status:no assertion criteria provided
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:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:1
Dec 18, 2018
Athena Diagnostics
Significance: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: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. -

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
0.058
BayesDel_addAF
Benign
-0.59
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
13
DANN
Benign
0.94
DEOGEN2
Benign
0.21
T;.;T;.;.;.;T
Eigen
Benign
-0.48
Eigen_PC
Benign
-0.36
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Benign
0.63
T;T;T;T;T;T;T
MetaRNN
Benign
0.0016
T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.6
L;.;.;L;.;L;.
PhyloP100
2.1
PrimateAI
Benign
0.26
T
PROVEAN
Benign
-0.67
N;.;N;N;N;N;N
REVEL
Benign
0.028
Sift
Benign
0.24
T;.;T;T;T;T;T
Sift4G
Benign
0.28
T;T;T;T;T;T;T
Polyphen
0.055
B;.;.;B;B;.;B
Vest4
0.040
MPC
0.13
ClinPred
0.0029
T
GERP RS
1.5
Varity_R
0.048
gMVP
0.065
Mutation Taster
=99/1
polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs17082709; hg19: chr6-152777095; COSMIC: COSV55119781; COSMIC: COSV55119781; API