NM_182961.4:c.8177+9C>T

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.8177+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 1,613,612 control chromosomes in the GnomAD database, including 3,926 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.089 ( 2039 hom., cov: 32)
Exomes 𝑓: 0.0093 ( 1887 hom. )

Consequence

SYNE1
NM_182961.4 intron

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.64

Publications

3 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 (BayesDel_noAF=-0.82).
BP6
Variant 6-152390271-G-A is Benign according to our data. Variant chr6-152390271-G-A is described in CliVar as Benign. Clinvar id is 130450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152390271-G-A is described in CliVar as Benign. Clinvar id is 130450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152390271-G-A is described in CliVar as Benign. Clinvar id is 130450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152390271-G-A is described in CliVar as Benign. Clinvar id is 130450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SYNE1NM_182961.4 linkc.8177+9C>T intron_variant Intron 53 of 145 ENST00000367255.10 NP_892006.3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SYNE1ENST00000367255.10 linkc.8177+9C>T intron_variant Intron 53 of 145 1 NM_182961.4 ENSP00000356224.5 Q8NF91-1
SYNE1ENST00000423061.6 linkc.8198+9C>T intron_variant Intron 53 of 145 1 ENSP00000396024.1 A0A0C4DG40
SYNE1ENST00000461872.6 linkn.8395+9C>T intron_variant Intron 51 of 54 1

Frequencies

GnomAD3 genomes
AF:
0.0886
AC:
13455
AN:
151930
Hom.:
2031
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.308
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0344
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000622
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0190
Gnomad NFE
AF:
0.00113
Gnomad OTH
AF:
0.0594
GnomAD2 exomes
AF:
0.0231
AC:
5811
AN:
251106
AF XY:
0.0170
show subpopulations
Gnomad AFR exome
AF:
0.314
Gnomad AMR exome
AF:
0.0143
Gnomad ASJ exome
AF:
0.000794
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000924
Gnomad NFE exome
AF:
0.00107
Gnomad OTH exome
AF:
0.0106
GnomAD4 exome
AF:
0.00931
AC:
13604
AN:
1461564
Hom.:
1887
Cov.:
33
AF XY:
0.00811
AC XY:
5897
AN XY:
727082
show subpopulations
African (AFR)
AF:
0.319
AC:
10646
AN:
33400
American (AMR)
AF:
0.0170
AC:
760
AN:
44712
Ashkenazi Jewish (ASJ)
AF:
0.000612
AC:
16
AN:
26136
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39692
South Asian (SAS)
AF:
0.000754
AC:
65
AN:
86250
European-Finnish (FIN)
AF:
0.0000562
AC:
3
AN:
53412
Middle Eastern (MID)
AF:
0.0159
AC:
90
AN:
5672
European-Non Finnish (NFE)
AF:
0.000633
AC:
704
AN:
1111926
Other (OTH)
AF:
0.0219
AC:
1319
AN:
60364
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.439
Heterozygous variant carriers
0
509
1018
1528
2037
2546
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
318
636
954
1272
1590
<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:
0.0887
AC:
13494
AN:
152048
Hom.:
2039
Cov.:
32
AF XY:
0.0860
AC XY:
6394
AN XY:
74352
show subpopulations
African (AFR)
AF:
0.308
AC:
12759
AN:
41398
American (AMR)
AF:
0.0342
AC:
523
AN:
15292
Ashkenazi Jewish (ASJ)
AF:
0.000288
AC:
1
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5176
South Asian (SAS)
AF:
0.000830
AC:
4
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10602
Middle Eastern (MID)
AF:
0.0204
AC:
6
AN:
294
European-Non Finnish (NFE)
AF:
0.00113
AC:
77
AN:
67976
Other (OTH)
AF:
0.0588
AC:
124
AN:
2108
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.502
Heterozygous variant carriers
0
467
934
1402
1869
2336
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
118
236
354
472
590
<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:
0.0317
Hom.:
1409
Bravo
AF:
0.102
Asia WGS
AF:
0.0220
AC:
75
AN:
3478
EpiCase
AF:
0.00115
EpiControl
AF:
0.00113

ClinVar

Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 16, 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. -

-
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. -

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 12, 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 12, 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
BayesDel_noAF
Benign
-0.82
CADD
Benign
0.012
DANN
Benign
0.50
PhyloP100
-1.6
Mutation Taster
=100/0
polymorphism (auto)

Splicing

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

Publications

Other links and lift over

dbSNP: rs56877632; hg19: chr6-152711406; API