NM_182914.3:c.12002G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBA1

The NM_182914.3(SYNE2):c.12002G>A(p.Trp4001*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0722 in 1,612,338 control chromosomes in the GnomAD database, including 5,029 homozygotes. Variant has been reported in ClinVar as Benign (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.089 ( 670 hom., cov: 32)

Exomes 𝑓: 0.070 ( 4359 hom. )

Consequence

SYNE2
NM_182914.3 stop_gained

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.36

Publications

39 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 -8 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BP6

Variant 14-64093374-G-A is Benign according to our data. Variant chr14-64093374-G-A is described in ClinVar as Benign. ClinVar VariationId is 130463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3 link	c.12002G>A	p.Trp4001*	stop_gained	Exon 61 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.12002G>A	p.Trp4001*	stop_gained	Exon 61 of 116	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes

AF:

0.0889

AC:

13508

AN:

152024

Hom.:

669

Cov.:

show subpopulations

Gnomad AFR

AF:

0.130

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0793

Gnomad ASJ

AF:

0.172

Gnomad EAS

AF:

0.109

Gnomad SAS

AF:

0.143

Gnomad FIN

AF:

0.0570

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0623

Gnomad OTH

AF:

0.0957

GnomAD2 exomes

AF:

0.0853

AC:

21442

AN:

251362

AF XY:

0.0874

show subpopulations

Gnomad AFR exome

AF:

0.131

Gnomad AMR exome

AF:

0.0484

Gnomad ASJ exome

AF:

0.181

Gnomad EAS exome

AF:

0.116

Gnomad FIN exome

AF:

0.0583

Gnomad NFE exome

AF:

0.0658

Gnomad OTH exome

AF:

0.0987

GnomAD4 exome

AF:

0.0704

AC:

102859

AN:

1460196

Hom.:

4359

Cov.:

AF XY:

0.0729

AC XY:

52954

AN XY:

726480

show subpopulations

African (AFR)

AF:

0.134

AC:

4486

AN:

33392

American (AMR)

AF:

0.0521

AC:

2330

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.185

AC:

4821

AN:

26104

East Asian (EAS)

AF:

0.114

AC:

4523

AN:

39680

South Asian (SAS)

AF:

0.137

AC:

11820

AN:

86184

European-Finnish (FIN)

AF:

0.0588

AC:

3141

AN:

53410

Middle Eastern (MID)

AF:

0.104

AC:

597

AN:

5762

European-Non Finnish (NFE)

AF:

0.0594

AC:

65948

AN:

1110630

Other (OTH)

AF:

0.0861

AC:

5193

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

4864

9727

14591

19454

24318

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2610

5220

7830

10440

13050

<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:

0.0888

AC:

13514

AN:

152142

Hom.:

670

Cov.:

AF XY:

0.0904

AC XY:

6723

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.130

AC:

5381

AN:

41512

American (AMR)

AF:

0.0792

AC:

1210

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.172

AC:

597

AN:

3466

East Asian (EAS)

AF:

0.109

AC:

564

AN:

5170

South Asian (SAS)

AF:

0.142

AC:

683

AN:

4810

European-Finnish (FIN)

AF:

0.0570

AC:

604

AN:

10588

Middle Eastern (MID)

AF:

0.116

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0623

AC:

4236

AN:

67994

Other (OTH)

AF:

0.0947

AC:

200

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

637

1274

1911

2548

3185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

162

324

486

648

810

<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:

0.0787

Hom.:

1140

Bravo

AF:

0.0904

TwinsUK

AF:

0.0569

AC:

211

ALSPAC

AF:

0.0633

AC:

244

ESP6500AA

AF:

0.115

AC:

505

ESP6500EA

AF:

0.0572

AC:

492

ExAC

AF:

0.0868

AC:

10535

Asia WGS

AF:

0.114

AC:

397

AN:

3478

EpiCase

AF:

0.0695

EpiControl

AF:

0.0743

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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. -

Oct 12, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25854761) -

Emery-Dreifuss muscular dystrophy 5, autosomal dominant

Benign:2

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. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.080

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

Eigen

Uncertain

0.39

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.80

PhyloP100

1.4

Vest4

0.75

GERP RS

1.9

Mutation Taster

=157/43

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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