rs45590135

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_182914.3(SYNE2):c.7163A>G(p.Glu2388Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,614,190 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E2388K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 34)

Exomes 𝑓: 0.0019 ( 9 hom. )

Consequence

SYNE2
NM_182914.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: -0.0260

Publications

2 publications found

Variant links:

Genes affected

SYNE2 (HGNC:17084): (spectrin repeat containing nuclear envelope protein 2) The protein encoded by this gene is a nuclear outer membrane protein that binds cytoplasmic F-actin. This binding tethers the nucleus to the cytoskeleton and aids in the maintenance of the structural integrity of the nucleus. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2009]

SYNE2 Gene-Disease associations (from GenCC):

autosomal dominant Emery-Dreifuss muscular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
left ventricular noncompaction
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
Emery-Dreifuss muscular dystrophy 5, autosomal dominant
Inheritance: Unknown, AD Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics

SYNE2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0042034388).

BP6

Variant 14-64031299-A-G is Benign according to our data. Variant chr14-64031299-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 252805.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00122 (186/152368) while in subpopulation NFE AF = 0.002 (136/68038). AF 95% confidence interval is 0.00173. There are 1 homozygotes in GnomAd4. There are 79 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High AC in GnomAd4 at 186 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182914.3. 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
	SYNE2	NM_182914.3	MANE Select	c.7163A>G	p.Glu2388Gly	missense	Exon 45 of 116	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.7163A>G	p.Glu2388Gly	missense	Exon 45 of 115	NP_055995.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYNE2	ENST00000555002.6	TSL:1 MANE Select	c.7163A>G	p.Glu2388Gly	missense	Exon 45 of 116	ENSP00000450831.2	Q8WXH0-2
SYNE2	ENST00000344113.8	TSL:1	c.7163A>G	p.Glu2388Gly	missense	Exon 45 of 115	ENSP00000341781.4	Q8WXH0-1
SYNE2	ENST00000358025.7	TSL:5	c.7163A>G	p.Glu2388Gly	missense	Exon 45 of 116	ENSP00000350719.3	Q8WXH0-2

Frequencies

GnomAD3 genomes

AF:

0.00122

AC:

186

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00200

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00168

AC:

419

AN:

248780

AF XY:

0.00184

show subpopulations

Gnomad AFR exome

AF:

0.000195

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00249

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000464

Gnomad NFE exome

AF:

0.00212

Gnomad OTH exome

AF:

0.00347

GnomAD4 exome

AF:

0.00187

AC:

2732

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00192

AC XY:

1394

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.00148

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00245

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00232

AC:

200

AN:

86254

European-Finnish (FIN)

AF:

0.000618

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00641

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00199

AC:

2217

AN:

1111994

Other (OTH)

AF:

0.00180

AC:

109

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

151

301

452

602

753

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

264

352

440

<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:

0.00122

AC:

186

AN:

152368

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.000264

AC:

AN:

41592

American (AMR)

AF:

0.00111

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00187

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00200

AC:

136

AN:

68038

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

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:

0.00153

Hom.:

Bravo

AF:

0.00114

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00170

AC:

ExAC

AF:

0.00155

AC:

187

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00180

EpiControl

AF:

0.00225

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

not provided (3)

Emery-Dreifuss muscular dystrophy 5, autosomal dominant (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.030

Eigen

Benign

-0.87

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.052

LIST_S2

Benign

0.64

M_CAP

Benign

0.020

MetaRNN

Benign

0.0042

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

-0.026

PrimateAI

Benign

0.22

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.051

Sift

Benign

0.12

Sift4G

Benign

0.36

Polyphen

0.0040

Vest4

0.060

MVP

0.24

MPC

0.054

ClinPred

0.0057

GERP RS

1.0

Varity_R

0.048

gMVP

0.15

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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