14-64137874-C-G

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.14734C>G(p.Pro4912Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0366 in 1,614,114 control chromosomes in the GnomAD database, including 1,243 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.038 ( 146 hom., cov: 32)

Exomes 𝑓: 0.036 ( 1097 hom. )

Consequence

SYNE2
NM_182914.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.01

Publications

15 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=0.0024898648).

BP6

Variant 14-64137874-C-G is Benign according to our data. Variant chr14-64137874-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0618 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3 link	c.14734C>G	p.Pro4912Ala	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.14734C>G	p.Pro4912Ala	missense_variant	Exon 79 of 116	1	NM_182914.3	ENSP00000450831.2		Q8WXH0-2A0A0C4DGK3

Frequencies

GnomAD3 genomes

AF:

0.0383

AC:

5827

AN:

152116

Hom.:

147

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0411

Gnomad AMI

AF:

0.140

Gnomad AMR

AF:

0.0340

Gnomad ASJ

AF:

0.0288

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.0124

Gnomad FIN

AF:

0.0494

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0396

Gnomad OTH

AF:

0.0398

GnomAD2 exomes

AF:

0.0329

AC:

8259

AN:

251326

AF XY:

0.0323

show subpopulations

Gnomad AFR exome

AF:

0.0413

Gnomad AMR exome

AF:

0.0213

Gnomad ASJ exome

AF:

0.0316

Gnomad EAS exome

AF:

0.000925

Gnomad FIN exome

AF:

0.0485

Gnomad NFE exome

AF:

0.0424

Gnomad OTH exome

AF:

0.0424

GnomAD4 exome

AF:

0.0365

AC:

53327

AN:

1461880

Hom.:

1097

Cov.:

AF XY:

0.0360

AC XY:

26165

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0457

AC:

1531

AN:

33480

American (AMR)

AF:

0.0222

AC:

994

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0282

AC:

737

AN:

26136

East Asian (EAS)

AF:

0.000277

AC:

AN:

39700

South Asian (SAS)

AF:

0.0135

AC:

1166

AN:

86258

European-Finnish (FIN)

AF:

0.0459

AC:

2450

AN:

53420

Middle Eastern (MID)

AF:

0.0673

AC:

388

AN:

5768

European-Non Finnish (NFE)

AF:

0.0395

AC:

43901

AN:

1111998

Other (OTH)

AF:

0.0356

AC:

2149

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

2994

5989

8983

11978

14972

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1586

3172

4758

6344

7930

<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:

0.0383

AC:

5828

AN:

152234

Hom.:

146

Cov.:

AF XY:

0.0381

AC XY:

2833

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0411

AC:

1706

AN:

41522

American (AMR)

AF:

0.0340

AC:

520

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0288

AC:

100

AN:

3472

East Asian (EAS)

AF:

0.00135

AC:

AN:

5182

South Asian (SAS)

AF:

0.0126

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0494

AC:

524

AN:

10600

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0396

AC:

2695

AN:

68026

Other (OTH)

AF:

0.0394

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

285

570

854

1139

1424

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<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:

0.0345

Hom.:

Bravo

AF:

0.0380

TwinsUK

AF:

0.0356

AC:

132

ALSPAC

AF:

0.0397

AC:

153

ESP6500AA

AF:

0.0397

AC:

175

ESP6500EA

AF:

0.0378

AC:

325

ExAC

AF:

0.0330

AC:

4003

Asia WGS

AF:

0.0140

AC:

AN:

3478

EpiCase

AF:

0.0407

EpiControl

AF:

0.0419

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jun 21, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 01, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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 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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.074

.;T;T;T;T

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.92

D;D;D;D;D

MetaRNN

Benign

0.0025

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;.;M;.;.

PhyloP100

1.0

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-3.4

D;.;D;D;D

REVEL

Benign

0.071

Sift

Uncertain

0.024

D;.;D;T;D

Sift4G

Uncertain

0.013

D;D;D;D;T

Polyphen

0.90

P;.;P;.;.

Vest4

0.19

MPC

0.18

ClinPred

0.040

GERP RS

4.0

Varity_R

0.17

gMVP

0.099

Mutation Taster

=97/3

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