rs36021513

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 14/20 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:6

Conservation

PhyloP100: 0.0550

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=0.0023183823).

BP6

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

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3404 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3 linkuse as main transcript	c.13254C>A	p.Asn4418Lys	missense_variant	69/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6 linkuse as main transcript	c.13254C>A	p.Asn4418Lys	missense_variant	69/116	1	NM_182914.3	P4	Q8WXH0-2

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

GnomAD3 exomes

AF:

0.0166

AC:

4159

AN:

251204

Hom.:

AF XY:

0.0169

AC XY:

2292

AN XY:

135776

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 SAS exome

AF:

0.0222

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

Gnomad4 AFR exome

AF:

0.0375

Gnomad4 AMR exome

AF:

0.00767

Gnomad4 ASJ exome

AF:

0.0184

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.0215

Gnomad4 FIN exome

AF:

0.0257

Gnomad4 NFE exome

AF:

0.0155

Gnomad4 OTH exome

AF:

0.0189

GnomAD4 genome

AF:

0.0224

AC:

3404

AN:

152162

Hom.:

Cov.:

AF XY:

0.0228

AC XY:

1693

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0370

Gnomad4 AMR

AF:

0.0186

Gnomad4 ASJ

AF:

0.0190

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0226

Gnomad4 FIN

AF:

0.0284

Gnomad4 NFE

AF:

0.0151

Gnomad4 OTH

AF:

0.0190

Alfa

AF:

0.0152

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:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 19, 2019	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

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

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;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N

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

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