rs36021513

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_182914.3(SYNE2):c.13254C>A(p.Asn4418Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0169 in 1,613,784 control chromosomes in the GnomAD database, including 264 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 44 hom., cov: 32)

Exomes 𝑓: 0.016 ( 220 hom. )

Consequence

SYNE2
NM_182914.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0550

Publications

11 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=0.0023183823).

BP6

Variant 14-64122107-C-A is Benign according to our data. Variant chr14-64122107-C-A is described in ClinVar as Benign. ClinVar VariationId is 130470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0224 (3404/152162) while in subpopulation AFR AF = 0.037 (1535/41504). AF 95% confidence interval is 0.0354. There are 44 homozygotes in GnomAd4. There are 1693 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 3404 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3 link	c.13254C>A	p.Asn4418Lys	missense_variant	Exon 69 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.13254C>A	p.Asn4418Lys	missense_variant	Exon 69 of 116	1	NM_182914.3	ENSP00000450831.2		Q8WXH0-2A0A0C4DGK3

Frequencies

GnomAD3 genomes

AF:

0.0223

AC:

3398

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0370

Gnomad AMI

AF:

0.0384

Gnomad AMR

AF:

0.0187

Gnomad ASJ

AF:

0.0190

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0226

Gnomad FIN

AF:

0.0284

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0151

Gnomad OTH

AF:

0.0173

GnomAD2 exomes

AF:

0.0166

AC:

4159

AN:

251204

AF XY:

0.0169

show subpopulations

Gnomad AFR exome

AF:

0.0382

Gnomad AMR exome

AF:

0.00729

Gnomad ASJ exome

AF:

0.0180

Gnomad EAS exome

AF:

0.000435

Gnomad FIN exome

AF:

0.0251

Gnomad NFE exome

AF:

0.0155

Gnomad OTH exome

AF:

0.0191

GnomAD4 exome

AF:

0.0163

AC:

23868

AN:

1461622

Hom.:

220

Cov.:

AF XY:

0.0164

AC XY:

11945

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.0375

AC:

1257

AN:

33480

American (AMR)

AF:

0.00767

AC:

343

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0184

AC:

481

AN:

26132

East Asian (EAS)

AF:

0.000302

AC:

AN:

39684

South Asian (SAS)

AF:

0.0215

AC:

1857

AN:

86252

European-Finnish (FIN)

AF:

0.0257

AC:

1369

AN:

53370

Middle Eastern (MID)

AF:

0.0248

AC:

143

AN:

5768

European-Non Finnish (NFE)

AF:

0.0155

AC:

17262

AN:

1111826

Other (OTH)

AF:

0.0189

AC:

1144

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

1331

2662

3992

5323

6654

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

662

1324

1986

2648

3310

<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:

0.0224

AC:

3404

AN:

152162

Hom.:

Cov.:

AF XY:

0.0228

AC XY:

1693

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.0370

AC:

1535

AN:

41504

American (AMR)

AF:

0.0186

AC:

285

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0190

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.0226

AC:

109

AN:

4820

European-Finnish (FIN)

AF:

0.0284

AC:

300

AN:

10566

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0151

AC:

1027

AN:

68014

Other (OTH)

AF:

0.0190

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

179

358

538

717

896

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0189

Hom.:

Bravo

AF:

0.0218

TwinsUK

AF:

0.0151

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.0340

AC:

150

ESP6500EA

AF:

0.0155

AC:

133

ExAC

AF:

0.0169

AC:

2052

Asia WGS

AF:

0.0180

AC:

AN:

3478

EpiCase

AF:

0.0160

EpiControl

AF:

0.0136

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 10, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Emery-Dreifuss muscular dystrophy 5, autosomal dominant

Benign:3

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 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. -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.055

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.73

CADD

Benign

1.8

(source)

DANN

Benign

0.50

DEOGEN2

Benign

0.0025

.;T;T;T;T;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.00085

LIST_S2

Benign

0.033

T;T;T;T;T;T

MetaRNN

Benign

0.0023

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.3

N;.;N;.;.;.

PhyloP100

0.055

PrimateAI

Benign

0.26

PROVEAN

Benign

0.36

N;.;N;N;N;N

REVEL

Benign

0.012

Sift

Benign

1.0

T;.;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T

Polyphen

0.0

B;.;B;.;.;.

Vest4

0.060

MutPred

0.28

Gain of ubiquitination at N4418 (P = 0.0075);.;Gain of ubiquitination at N4418 (P = 0.0075);.;.;.;

MPC

0.052

ClinPred

0.00030

GERP RS

-0.77

Varity_R

0.024

gMVP

0.080

Mutation Taster

=99/1

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