14-64137874-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 130475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64137874-C-G is described in Lovd as [Benign].

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

GnomAD3 exomes

AF:

0.0329

AC:

8259

AN:

251326

Hom.:

176

AF XY:

0.0323

AC XY:

4383

AN XY:

135816

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 SAS exome

AF:

0.0126

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

Gnomad4 AFR exome

AF:

0.0457

Gnomad4 AMR exome

AF:

0.0222

Gnomad4 ASJ exome

AF:

0.0282

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.0135

Gnomad4 FIN exome

AF:

0.0459

Gnomad4 NFE exome

AF:

0.0395

Gnomad4 OTH exome

AF:

0.0356

GnomAD4 genome

AF:

0.0383

AC:

5828

AN:

152234

Hom.:

146

Cov.:

AF XY:

0.0381

AC XY:

2833

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.0411

Gnomad4 AMR

AF:

0.0340

Gnomad4 ASJ

AF:

0.0288

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.0126

Gnomad4 FIN

AF:

0.0494

Gnomad4 NFE

AF:

0.0396

Gnomad4 OTH

AF:

0.0394

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

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. -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

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. -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

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;.;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over