chr6-152214971-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_182961.4(SYNE1):​c.22281C>A​(p.Ile7427Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000937 in 1,614,094 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0053 ( 11 hom., cov: 32)
Exomes 𝑓: 0.00049 ( 6 hom. )

Consequence

SYNE1
NM_182961.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.47

Publications

1 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 -19 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.31).
BP6
Variant 6-152214971-G-T is Benign according to our data. Variant chr6-152214971-G-T is described in ClinVar as [Benign]. Clinvar id is 355825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=3.47 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00527 (802/152282) while in subpopulation AFR AF = 0.0183 (762/41548). AF 95% confidence interval is 0.0173. There are 11 homozygotes in GnomAd4. There are 352 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 11 AR,AD gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SYNE1NM_182961.4 linkc.22281C>A p.Ile7427Ile synonymous_variant Exon 122 of 146 ENST00000367255.10 NP_892006.3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SYNE1ENST00000367255.10 linkc.22281C>A p.Ile7427Ile synonymous_variant Exon 122 of 146 1 NM_182961.4 ENSP00000356224.5 Q8NF91-1

Frequencies

GnomAD3 genomes
AF:
0.00525
AC:
799
AN:
152164
Hom.:
11
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0183
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00479
GnomAD2 exomes
AF:
0.00124
AC:
311
AN:
251312
AF XY:
0.000920
show subpopulations
Gnomad AFR exome
AF:
0.0168
Gnomad AMR exome
AF:
0.000954
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.000486
AC:
711
AN:
1461812
Hom.:
6
Cov.:
32
AF XY:
0.000426
AC XY:
310
AN XY:
727214
show subpopulations
African (AFR)
AF:
0.0167
AC:
559
AN:
33476
American (AMR)
AF:
0.00105
AC:
47
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26130
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39692
South Asian (SAS)
AF:
0.0000232
AC:
2
AN:
86250
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53414
Middle Eastern (MID)
AF:
0.00121
AC:
7
AN:
5766
European-Non Finnish (NFE)
AF:
0.00000989
AC:
11
AN:
1111972
Other (OTH)
AF:
0.00141
AC:
85
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.483
Heterozygous variant carriers
0
40
81
121
162
202
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
22
44
66
88
110
<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:
0.00527
AC:
802
AN:
152282
Hom.:
11
Cov.:
32
AF XY:
0.00473
AC XY:
352
AN XY:
74472
show subpopulations
African (AFR)
AF:
0.0183
AC:
762
AN:
41548
American (AMR)
AF:
0.00196
AC:
30
AN:
15292
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5186
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10610
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
292
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68034
Other (OTH)
AF:
0.00474
AC:
10
AN:
2110
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.509
Heterozygous variant carriers
0
41
81
122
162
203
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
10
20
30
40
50
<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:
0.00265
Hom.:
1
Bravo
AF:
0.00616
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Mar 13, 2018
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. -

Feb 01, 2024
Athena Diagnostics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant Benign:1
Jan 20, 2025
Labcorp Genetics (formerly Invitae), Labcorp
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
-0.31
CADD
Benign
6.4
DANN
Benign
0.77
PhyloP100
3.5
Mutation Taster
=99/1
polymorphism

Splicing

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

Publications

Other links and lift over

dbSNP: rs139362680; hg19: chr6-152536106; COSMIC: COSV54960988; API