rs117480635

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_182961.4(SYNE1):c.7976C>A(p.Thr2659Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,614,040 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T2659T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0025 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0035 ( 14 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

Conservation

PhyloP100: 3.18

Publications

12 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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics, Orphanet, PanelApp Australia, G2P
Emery-Dreifuss muscular dystrophy 4, autosomal dominant
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Illumina, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
arthrogryposis multiplex congenita 3, myogenic type
Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00968653).

BP6

Variant 6-152391305-G-T is Benign according to our data. Variant chr6-152391305-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197940.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.7976C>A	p.Thr2659Asn	missense	Exon 52 of 146	NP_892006.3	Q8NF91-1
	SYNE1	NM_033071.5		c.7997C>A	p.Thr2666Asn	missense	Exon 52 of 146	NP_149062.2	Q8NF91-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.7976C>A	p.Thr2659Asn	missense	Exon 52 of 146	ENSP00000356224.5	Q8NF91-1
SYNE1	ENST00000423061.6	TSL:1	c.7997C>A	p.Thr2666Asn	missense	Exon 52 of 146	ENSP00000396024.1	A0A0C4DG40
SYNE1	ENST00000461872.6	TSL:1	n.8194C>A		non_coding_transcript_exon	Exon 50 of 55

Frequencies

GnomAD3 genomes

AF:

0.00247

AC:

376

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000773

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00420

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00229

AC:

574

AN:

250794

AF XY:

0.00247

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00194

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.00385

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00346

AC:

5051

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00334

AC XY:

2429

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

33478

American (AMR)

AF:

0.00228

AC:

102

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000765

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.00167

AC:

144

AN:

86258

European-Finnish (FIN)

AF:

0.000487

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00416

AC:

4629

AN:

1111990

Other (OTH)

AF:

0.00210

AC:

127

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

319

637

956

1274

1593

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

352

528

704

880

<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:

0.00248

AC:

377

AN:

152198

Hom.:

Cov.:

AF XY:

0.00243

AC XY:

181

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.000770

AC:

AN:

41536

American (AMR)

AF:

0.00321

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00145

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00421

AC:

286

AN:

68008

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00323

Hom.:

Bravo

AF:

0.00269

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.00239

AC:

290

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00387

EpiControl

AF:

0.00379

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Arthrogryposis syndrome (1)

Autosomal recessive ataxia, Beauce type (1)

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

Emery-Dreifuss muscular dystrophy 4, autosomal dominant (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.31

Eigen

Benign

-0.070

Eigen_PC

Benign

-0.040

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.011

MetaRNN

Benign

0.0097

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

3.2

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.9

REVEL

Benign

0.11

Sift

Benign

0.24

Sift4G

Uncertain

0.024

Polyphen

0.41

Vest4

0.26

MVP

0.52

MPC

0.30

ClinPred

0.027

GERP RS

5.0

Varity_R

0.10

gMVP

0.45

Mutation Taster

=78/22

polymorphism

(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

Computational scores

Splicing

Publications

Other links and lift over