rs12881815

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.14737G>A(p.Glu4913Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0487 in 1,614,142 control chromosomes in the GnomAD database, including 2,238 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 149 hom., cov: 32)

Exomes 𝑓: 0.050 ( 2089 hom. )

Consequence

SYNE2
NM_182914.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 4.37

Publications

21 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 links:

ESR2 (HGNC:3468): (estrogen receptor 2) This gene encodes a member of the family of estrogen receptors and superfamily of nuclear receptor transcription factors. The gene product contains an N-terminal DNA binding domain and C-terminal ligand binding domain and is localized to the nucleus, cytoplasm, and mitochondria. Upon binding to 17beta-estradiol or related ligands, the encoded protein forms homo- or hetero-dimers that interact with specific DNA sequences to activate transcription. Some isoforms dominantly inhibit the activity of other estrogen receptor family members. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been fully characterized. [provided by RefSeq, Jul 2008]

ESR2 Gene-Disease associations (from GenCC):

male infertility with azoospermia or oligozoospermia due to single gene mutation
Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center
familial medullary thyroid carcinoma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ovarian dysgenesis 8
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ESR2 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=0.002101481).

BP6

Variant 14-64137877-G-A is Benign according to our data. Variant chr14-64137877-G-A is described in ClinVar as Benign. ClinVar VariationId is 130476.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0634 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3 link	c.14737G>A	p.Glu4913Lys	missense_variant	Exon 79 of 116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6 link	c.14737G>A	p.Glu4913Lys	missense_variant	Exon 79 of 116	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes

AF:

0.0366

AC:

5564

AN:

152144

Hom.:

150

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00937

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0672

Gnomad ASJ

AF:

0.0182

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0141

Gnomad FIN

AF:

0.0369

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0523

Gnomad OTH

AF:

0.0274

GnomAD2 exomes

AF:

0.0432

AC:

10849

AN:

251326

AF XY:

0.0417

show subpopulations

Gnomad AFR exome

AF:

0.00966

Gnomad AMR exome

AF:

0.0866

Gnomad ASJ exome

AF:

0.0239

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.0400

Gnomad NFE exome

AF:

0.0518

Gnomad OTH exome

AF:

0.0414

GnomAD4 exome

AF:

0.0499

AC:

72984

AN:

1461880

Hom.:

2089

Cov.:

AF XY:

0.0486

AC XY:

35340

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00759

AC:

254

AN:

33480

American (AMR)

AF:

0.0851

AC:

3804

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0246

AC:

643

AN:

26136

East Asian (EAS)

AF:

0.000176

AC:

AN:

39700

South Asian (SAS)

AF:

0.0155

AC:

1340

AN:

86258

European-Finnish (FIN)

AF:

0.0405

AC:

2163

AN:

53418

Middle Eastern (MID)

AF:

0.00850

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0561

AC:

62330

AN:

1112000

Other (OTH)

AF:

0.0396

AC:

2394

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

4223

8446

12669

16892

21115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2340

4680

7020

9360

11700

<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:

0.0365

AC:

5558

AN:

152262

Hom.:

149

Cov.:

AF XY:

0.0359

AC XY:

2674

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.00934

AC:

388

AN:

41550

American (AMR)

AF:

0.0668

AC:

1022

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0182

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0139

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0369

AC:

392

AN:

10610

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0523

AC:

3556

AN:

68022

Other (OTH)

AF:

0.0271

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

274

547

821

1094

1368

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0462

Hom.:

920

Bravo

AF:

0.0381

TwinsUK

AF:

0.0569

AC:

211

ALSPAC

AF:

0.0503

AC:

194

ESP6500AA

AF:

0.0104

AC:

ESP6500EA

AF:

0.0506

AC:

435

ExAC

AF:

0.0408

AC:

4955

Asia WGS

AF:

0.00751

AC:

AN:

3478

EpiCase

AF:

0.0478

EpiControl

AF:

0.0450

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Emery-Dreifuss muscular dystrophy 5, autosomal dominant

Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:1

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

.;T;T;T;T

Eigen

Benign

0.079

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.57

LIST_S2

Uncertain

0.90

D;D;D;D;D

MetaRNN

Benign

0.0021

T;T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.0

M;.;M;.;.

PhyloP100

4.4

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.0

D;.;D;D;D

REVEL

Benign

0.14

Sift

Benign

0.069

T;.;T;T;T

Sift4G

Uncertain

0.050

T;D;D;D;T

Polyphen

0.68

P;.;P;.;.

Vest4

0.35

MPC

0.33

ClinPred

0.037

GERP RS

5.0

Varity_R

0.26

gMVP

0.31

Mutation Taster

=88/12

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over