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.22809C>T(p.Leu7603Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,614,156 control chromosomes in the GnomAD database, including 301 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 26 hom., cov: 32)

Exomes 𝑓: 0.017 ( 275 hom. )

Consequence

SYNE1
NM_182961.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.277

Publications

4 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BP6

Variant 6-152207987-G-A is Benign according to our data. Variant chr6-152207987-G-A is described in ClinVar as Benign. ClinVar VariationId is 130424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.277 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0126 (1926/152334) while in subpopulation NFE AF = 0.0194 (1318/68036). AF 95% confidence interval is 0.0185. There are 26 homozygotes in GnomAd4. There are 941 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 26 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE1	NM_182961.4	MANE Select	c.22809C>T	p.Leu7603Leu	synonymous	Exon 125 of 146	NP_892006.3
	SYNE1	NM_033071.5		c.22596C>T	p.Leu7532Leu	synonymous	Exon 124 of 146	NP_149062.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SYNE1	ENST00000367255.10	TSL:1 MANE Select	c.22809C>T	p.Leu7603Leu	synonymous	Exon 125 of 146	ENSP00000356224.5
SYNE1	ENST00000423061.6	TSL:1	c.22596C>T	p.Leu7532Leu	synonymous	Exon 124 of 146	ENSP00000396024.1
SYNE1	ENST00000367251.7	TSL:1	c.1575C>T	p.Leu525Leu	synonymous	Exon 10 of 31	ENSP00000356220.3

Frequencies

GnomAD3 genomes

AF:

0.0127

AC:

1926

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00347

Gnomad AMI

AF:

0.0560

Gnomad AMR

AF:

0.00595

Gnomad ASJ

AF:

0.0109

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0253

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0194

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.0113

AC:

2852

AN:

251302

AF XY:

0.0116

show subpopulations

Gnomad AFR exome

AF:

0.00344

Gnomad AMR exome

AF:

0.00422

Gnomad ASJ exome

AF:

0.0100

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.0193

Gnomad NFE exome

AF:

0.0176

Gnomad OTH exome

AF:

0.00994

GnomAD4 exome

AF:

0.0170

AC:

24798

AN:

1461822

Hom.:

275

Cov.:

AF XY:

0.0167

AC XY:

12127

AN XY:

727220

show subpopulations

African (AFR)

AF:

0.00278

AC:

AN:

33480

American (AMR)

AF:

0.00440

AC:

197

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0112

AC:

292

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39690

South Asian (SAS)

AF:

0.00253

AC:

218

AN:

86256

European-Finnish (FIN)

AF:

0.0201

AC:

1075

AN:

53416

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0198

AC:

22050

AN:

1111962

Other (OTH)

AF:

0.0141

AC:

852

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

1361

2723

4084

5446

6807

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

840

1680

2520

3360

4200

<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:

0.0126

AC:

1926

AN:

152334

Hom.:

Cov.:

AF XY:

0.0126

AC XY:

941

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00346

AC:

144

AN:

41582

American (AMR)

AF:

0.00595

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0109

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00124

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0253

AC:

269

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0194

AC:

1318

AN:

68036

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

190

284

379

474

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0150

Hom.:

Bravo

AF:

0.0107

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (2)

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)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

7.2

(source)

DANN

Benign

0.72

PhyloP100

0.28

Mutation Taster

=99/1

polymorphism

(source)

Splicing

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

Publications

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rs34630198

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