Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_182961.4(SYNE1):c.25038T>C(p.Arg8346Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.581 in 1,613,882 control chromosomes in the GnomAD database, including 275,698 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.62 ( 30299 hom., cov: 32)

Exomes 𝑓: 0.58 ( 245399 hom. )

Consequence

SYNE1
NM_182961.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.583

Publications

26 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

SYNE1 links:

ENSG00000300811 (HGNC:):

ENSG00000300811 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BP6

Variant 6-152143704-A-G is Benign according to our data. Variant chr6-152143704-A-G is described in ClinVar as Benign. ClinVar VariationId is 130430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.583 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.746 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182961.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SYNE1	NM_182961.4	MANE Select	c.25038T>C	p.Arg8346Arg	synonymous	Exon 138 of 146	NP_892006.3
SYNE1	NM_001347702.2	MANE Plus Clinical	c.1572T>C	p.Arg524Arg	synonymous	Exon 10 of 18	NP_001334631.1
SYNE1	NM_033071.5		c.24894T>C	p.Arg8298Arg	synonymous	Exon 138 of 146	NP_149062.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.25038T>C	p.Arg8346Arg	synonymous	Exon 138 of 146	ENSP00000356224.5
SYNE1	ENST00000354674.5	TSL:5 MANE Plus Clinical	c.1572T>C	p.Arg524Arg	synonymous	Exon 10 of 18	ENSP00000346701.4
SYNE1	ENST00000423061.6	TSL:1	c.24894T>C	p.Arg8298Arg	synonymous	Exon 138 of 146	ENSP00000396024.1

Frequencies

GnomAD3 genomes

AF:

0.624

AC:

94736

AN:

151914

Hom.:

30249

Cov.:

show subpopulations

Gnomad AFR

AF:

0.753

Gnomad AMI

AF:

0.512

Gnomad AMR

AF:

0.672

Gnomad ASJ

AF:

0.570

Gnomad EAS

AF:

0.698

Gnomad SAS

AF:

0.684

Gnomad FIN

AF:

0.482

Gnomad MID

AF:

0.525

Gnomad NFE

AF:

0.550

Gnomad OTH

AF:

0.637

GnomAD2 exomes

AF:

0.611

AC:

153614

AN:

251476

AF XY:

0.607

show subpopulations

Gnomad AFR exome

AF:

0.758

Gnomad AMR exome

AF:

0.715

Gnomad ASJ exome

AF:

0.569

Gnomad EAS exome

AF:

0.693

Gnomad FIN exome

AF:

0.486

Gnomad NFE exome

AF:

0.552

Gnomad OTH exome

AF:

0.584

GnomAD4 exome

AF:

0.576

AC:

842418

AN:

1461848

Hom.:

245399

Cov.:

AF XY:

0.578

AC XY:

420431

AN XY:

727234

show subpopulations

African (AFR)

AF:

0.756

AC:

25325

AN:

33480

American (AMR)

AF:

0.710

AC:

31769

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.568

AC:

14837

AN:

26136

East Asian (EAS)

AF:

0.713

AC:

28303

AN:

39698

South Asian (SAS)

AF:

0.691

AC:

59584

AN:

86258

European-Finnish (FIN)

AF:

0.495

AC:

26459

AN:

53418

Middle Eastern (MID)

AF:

0.585

AC:

3372

AN:

5768

European-Non Finnish (NFE)

AF:

0.555

AC:

617065

AN:

1111972

Other (OTH)

AF:

0.591

AC:

35704

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

23154

46307

69461

92614

115768

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17548

35096

52644

70192

87740

<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:

0.624

AC:

94853

AN:

152034

Hom.:

30299

Cov.:

AF XY:

0.624

AC XY:

46379

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.753

AC:

31250

AN:

41480

American (AMR)

AF:

0.673

AC:

10279

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.570

AC:

1979

AN:

3470

East Asian (EAS)

AF:

0.698

AC:

3606

AN:

5168

South Asian (SAS)

AF:

0.683

AC:

3290

AN:

4820

European-Finnish (FIN)

AF:

0.482

AC:

5069

AN:

10524

Middle Eastern (MID)

AF:

0.534

AC:

157

AN:

294

European-Non Finnish (NFE)

AF:

0.550

AC:

37403

AN:

67972

Other (OTH)

AF:

0.639

AC:

1353

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1804

3607

5411

7214

9018

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

766

1532

2298

3064

3830

<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:

0.584

Hom.:

114049

Bravo

AF:

0.643

Asia WGS

AF:

0.697

AC:

2424

AN:

3478

EpiCase

AF:

0.551

EpiControl

AF:

0.550

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Autosomal recessive ataxia, Beauce type (2)

Emery-Dreifuss muscular dystrophy 4, autosomal dominant (2)

Arthrogryposis multiplex congenita 3, myogenic type (1)

Autosomal recessive ataxia, Beauce type;C2751807:Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

5.8

(source)

DANN

Benign

0.52

PhyloP100

0.58

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over