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GeneBe

rs117501809

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_182961.4(SYNE1):ā€‹c.12442G>Cā€‹(p.Asp4148His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0306 in 1,614,180 control chromosomes in the GnomAD database, including 913 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā˜…ā˜…). Synonymous variant affecting the same amino acid position (i.e. D4148D) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.022 ( 45 hom., cov: 32)
Exomes š‘“: 0.031 ( 868 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

5
8
5

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 7.90
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2
?
    PP2 - Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease
Missense variant where missense usually causes diseases, SYNE1
BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.0064047575).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 6-152336927-C-G is Benign according to our data. Variant chr6-152336927-C-G is described in ClinVar as [Benign]. Clinvar id is 130401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-152336927-C-G is described in Lovd as [Benign].
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0219 (3339/152338) while in subpopulation NFE AF= 0.0344 (2343/68036). AF 95% confidence interval is 0.0333. There are 45 homozygotes in gnomad4. There are 1570 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd4 at 3339 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SYNE1NM_182961.4 linkuse as main transcriptc.12442G>C p.Asp4148His missense_variant 76/146 ENST00000367255.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SYNE1ENST00000367255.10 linkuse as main transcriptc.12442G>C p.Asp4148His missense_variant 76/1461 NM_182961.4 P1Q8NF91-1
SYNE1ENST00000423061.6 linkuse as main transcriptc.12229G>C p.Asp4077His missense_variant 75/1461
SYNE1ENST00000471834.1 linkuse as main transcriptn.5580G>C non_coding_transcript_exon_variant 19/191

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0219
AC:
3339
AN:
152220
Hom.:
45
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00511
Gnomad AMI
AF:
0.0603
Gnomad AMR
AF:
0.0117
Gnomad ASJ
AF:
0.00980
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.0275
Gnomad FIN
AF:
0.0322
Gnomad MID
AF:
0.0190
Gnomad NFE
AF:
0.0344
Gnomad OTH
AF:
0.0163
GnomAD3 exomes
AF:
0.0253
AC:
6362
AN:
251382
Hom.:
110
AF XY:
0.0267
AC XY:
3631
AN XY:
135860
show subpopulations
Gnomad AFR exome
AF:
0.00597
Gnomad AMR exome
AF:
0.00966
Gnomad ASJ exome
AF:
0.00893
Gnomad EAS exome
AF:
0.000163
Gnomad SAS exome
AF:
0.0313
Gnomad FIN exome
AF:
0.0314
Gnomad NFE exome
AF:
0.0355
Gnomad OTH exome
AF:
0.0257
GnomAD4 exome
AF:
0.0315
AC:
46007
AN:
1461842
Hom.:
868
Cov.:
29
AF XY:
0.0315
AC XY:
22885
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.00493
Gnomad4 AMR exome
AF:
0.0101
Gnomad4 ASJ exome
AF:
0.00899
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0319
Gnomad4 FIN exome
AF:
0.0308
Gnomad4 NFE exome
AF:
0.0350
Gnomad4 OTH exome
AF:
0.0273
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0219
AC:
3339
AN:
152338
Hom.:
45
Cov.:
32
AF XY:
0.0211
AC XY:
1570
AN XY:
74492
show subpopulations
Gnomad4 AFR
AF:
0.00510
Gnomad4 AMR
AF:
0.0116
Gnomad4 ASJ
AF:
0.00980
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.0280
Gnomad4 FIN
AF:
0.0322
Gnomad4 NFE
AF:
0.0344
Gnomad4 OTH
AF:
0.0161
Alfa
AF:
0.0287
Hom.:
60
Bravo
AF:
0.0192
TwinsUK
AF:
0.0345
AC:
128
ALSPAC
AF:
0.0324
AC:
125
ESP6500AA
AF:
0.00681
AC:
30
ESP6500EA
AF:
0.0326
AC:
280
ExAC
?
    Exome Aggregation Consortium database
AF:
0.0272
AC:
3298
Asia WGS
AF:
0.00924
AC:
32
AN:
3478
EpiCase
AF:
0.0343
EpiControl
AF:
0.0319

ClinVar

Significance: Benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
Likely benign, no assertion criteria providedclinical testingGenetic 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, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 11, 2016This 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. -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant Benign:1
Benign, criteria provided, single submitterclinical testingInvitaeJan 29, 2024- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsMay 07, 2019- -
Autosomal recessive ataxia, Beauce type Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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
Pathogenic
0.64
BayesDel_addAF
Benign
-0.35
T
BayesDel_noAF
Benign
-0.24
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.58
D;.;T
Eigen
Pathogenic
0.82
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.93
D;D;D
MetaRNN
Benign
0.0064
T;T;T
MetaSVM
Benign
-0.51
T
MutationAssessor
Uncertain
2.1
M;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.63
T
PROVEAN
Uncertain
-2.8
D;.;D
REVEL
Uncertain
0.32
Sift
Uncertain
0.0020
D;.;D
Sift4G
Pathogenic
0.0010
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.68
MPC
0.66
ClinPred
0.011
T
GERP RS
5.5
Varity_R
0.58
gMVP
0.46

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.

Other links and lift over

dbSNP: rs117501809; hg19: chr6-152658062; COSMIC: COSV99560137; COSMIC: COSV99560137; API