rs35079654

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_182961.4(SYNE1):c.19991C>T(p.Thr6664Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000617 in 1,614,198 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00036 ( 0 hom. )

Consequence

SYNE1
NM_182961.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.27

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037666261).

BP6

Variant 6-152239609-G-A is Benign according to our data. Variant chr6-152239609-G-A is described in ClinVar as Benign. ClinVar VariationId is 448569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.19991C>T	p.Thr6664Ile	missense	Exon 108 of 146	NP_892006.3
	SYNE1	NM_033071.5		c.19778C>T	p.Thr6593Ile	missense	Exon 107 of 146	NP_149062.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.19991C>T	p.Thr6664Ile	missense	Exon 108 of 146	ENSP00000356224.5
SYNE1	ENST00000423061.6	TSL:1	c.19778C>T	p.Thr6593Ile	missense	Exon 107 of 146	ENSP00000396024.1
SYNE1	ENST00000367256.9	TSL:1	n.3683C>T		non_coding_transcript_exon	Exon 23 of 61

Frequencies

GnomAD3 genomes

AF:

0.00309

AC:

470

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0105

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.000871

AC:

219

AN:

251388

AF XY:

0.000729

show subpopulations

Gnomad AFR exome

AF:

0.0111

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000356

AC:

520

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000345

AC XY:

251

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0105

AC:

350

AN:

33480

American (AMR)

AF:

0.000850

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000421

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000513

AC:

AN:

1112010

Other (OTH)

AF:

0.000911

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

107

142

178

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.00313

AC:

476

AN:

152310

Hom.:

Cov.:

AF XY:

0.00305

AC XY:

227

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0106

AC:

440

AN:

41564

American (AMR)

AF:

0.00137

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68032

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

103

129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00130

Hom.:

Bravo

AF:

0.00373

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.0111

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000997

AC:

121

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

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

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.18

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0038

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PhyloP100

2.3

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.041

Sift

Benign

0.15

Sift4G

Benign

0.076

Polyphen

0.018

Vest4

0.34

MVP

0.28

MPC

0.15

ClinPred

0.015

GERP RS

3.5

Varity_R

0.063

gMVP

0.092

Mutation Taster

=77/23

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over