rs4027405

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_182914.3(SYNE2):c.7183G>A(p.Ala2395Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.912 in 1,613,968 control chromosomes in the GnomAD database, including 672,553 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A2395A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.88 ( 58781 hom., cov: 32)

Exomes 𝑓: 0.92 ( 613772 hom. )

Consequence

SYNE2
NM_182914.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.85

Publications

36 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
Emery-Dreifuss muscular dystrophy 5, autosomal dominant
Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics
left ventricular noncompaction
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

SYNE2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.149704E-7).

BP6

Variant 14-64031319-G-A is Benign according to our data. Variant chr14-64031319-G-A is described in ClinVar as Benign. ClinVar VariationId is 130511.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

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.7183G>A	p.Ala2395Thr	missense	Exon 45 of 116	NP_878918.2
	SYNE2	NM_015180.6		c.7183G>A	p.Ala2395Thr	missense	Exon 45 of 115	NP_055995.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SYNE2	ENST00000555002.6	TSL:1 MANE Select	c.7183G>A	p.Ala2395Thr	missense	Exon 45 of 116	ENSP00000450831.2
SYNE2	ENST00000344113.8	TSL:1	c.7183G>A	p.Ala2395Thr	missense	Exon 45 of 115	ENSP00000341781.4
SYNE2	ENST00000358025.7	TSL:5	c.7183G>A	p.Ala2395Thr	missense	Exon 45 of 116	ENSP00000350719.3

Frequencies

GnomAD3 genomes

AF:

0.876

AC:

133309

AN:

152112

Hom.:

58734

Cov.:

show subpopulations

Gnomad AFR

AF:

0.780

Gnomad AMI

AF:

0.924

Gnomad AMR

AF:

0.906

Gnomad ASJ

AF:

0.845

Gnomad EAS

AF:

0.857

Gnomad SAS

AF:

0.840

Gnomad FIN

AF:

0.927

Gnomad MID

AF:

0.839

Gnomad NFE

AF:

0.926

Gnomad OTH

AF:

0.878

GnomAD2 exomes

AF:

0.895

AC:

222525

AN:

248624

AF XY:

0.894

show subpopulations

Gnomad AFR exome

AF:

0.773

Gnomad AMR exome

AF:

0.942

Gnomad ASJ exome

AF:

0.829

Gnomad EAS exome

AF:

0.842

Gnomad FIN exome

AF:

0.924

Gnomad NFE exome

AF:

0.920

Gnomad OTH exome

AF:

0.881

GnomAD4 exome

AF:

0.916

AC:

1338252

AN:

1461738

Hom.:

613772

Cov.:

AF XY:

0.913

AC XY:

664192

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.765

AC:

25603

AN:

33480

American (AMR)

AF:

0.938

AC:

41944

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.829

AC:

21657

AN:

26130

East Asian (EAS)

AF:

0.868

AC:

34445

AN:

39692

South Asian (SAS)

AF:

0.850

AC:

73323

AN:

86250

European-Finnish (FIN)

AF:

0.927

AC:

49454

AN:

53360

Middle Eastern (MID)

AF:

0.838

AC:

4835

AN:

5768

European-Non Finnish (NFE)

AF:

0.929

AC:

1032957

AN:

1111952

Other (OTH)

AF:

0.895

AC:

54034

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

6473

12946

19419

25892

32365

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21540

43080

64620

86160

107700

<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:

0.876

AC:

133409

AN:

152230

Hom.:

58781

Cov.:

AF XY:

0.875

AC XY:

65131

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.780

AC:

32364

AN:

41494

American (AMR)

AF:

0.906

AC:

13858

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.845

AC:

2935

AN:

3472

East Asian (EAS)

AF:

0.857

AC:

4443

AN:

5186

South Asian (SAS)

AF:

0.840

AC:

4056

AN:

4826

European-Finnish (FIN)

AF:

0.927

AC:

9829

AN:

10606

Middle Eastern (MID)

AF:

0.837

AC:

246

AN:

294

European-Non Finnish (NFE)

AF:

0.926

AC:

62977

AN:

68026

Other (OTH)

AF:

0.879

AC:

1858

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

843

1685

2528

3370

4213

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

896

1792

2688

3584

4480

<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:

0.904

Hom.:

208423

Bravo

AF:

0.870

TwinsUK

AF:

0.932

AC:

3457

ALSPAC

AF:

0.923

AC:

3557

ESP6500AA

AF:

0.782

AC:

3013

ESP6500EA

AF:

0.923

AC:

7631

ExAC

AF:

0.892

AC:

107745

Asia WGS

AF:

0.850

AC:

2956

AN:

3478

EpiCase

AF:

0.917

EpiControl

AF:

0.912

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Emery-Dreifuss muscular dystrophy 5, autosomal dominant (3)

not provided (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.0098

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.064

LIST_S2

Benign

0.75

MetaRNN

Benign

9.1e-7

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.1

PhyloP100

1.8

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.52

REVEL

Benign

0.057

Sift

Benign

0.25

Sift4G

Benign

0.32

Polyphen

0.0090

Vest4

0.025

MPC

0.25

ClinPred

0.013

GERP RS

3.2

Varity_R

0.025

gMVP

0.12

Mutation Taster

=273/27

polymorphism (auto)

(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