rs141741640

Positions:

chr14-64214272-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_182914.3(SYNE2):c.19135C>T(p.Arg6379Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,613,902 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 5 hom. )

Consequence

SYNE2
NM_182914.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8O:1

Conservation

PhyloP100: 0.993

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:

SYNE2 (HGNC:):

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015034795).

BP6

Variant 14-64214272-C-T is Benign according to our data. Variant chr14-64214272-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193779.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=1, not_provided=1, Benign=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0013 (198/152008) while in subpopulation NFE AF= 0.00247 (168/67988). AF 95% confidence interval is 0.00217. There are 0 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 198 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE2	NM_182914.3 linkuse as main transcript	c.19135C>T	p.Arg6379Cys	missense_variant	106/116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6 linkuse as main transcript	c.19135C>T	p.Arg6379Cys	missense_variant	106/116	1	NM_182914.3	ENSP00000450831.2		Q8WXH0-2A0A0C4DGK3

Frequencies

GnomAD3 genomes

AF:

0.00130

AC:

198

AN:

151892

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000339

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000395

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000757

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00247

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00132

AC:

333

AN:

251488

Hom.:

AF XY:

0.00133

AC XY:

181

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000598

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00180

Gnomad NFE exome

AF:

0.00228

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.00188

AC:

2744

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00178

AC XY:

1292

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.000402

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00155

Gnomad4 NFE exome

AF:

0.00230

Gnomad4 OTH exome

AF:

0.000861

GnomAD4 genome

AF:

0.00130

AC:

198

AN:

152008

Hom.:

Cov.:

AF XY:

0.00113

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.000338

Gnomad4 AMR

AF:

0.000394

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000757

Gnomad4 NFE

AF:

0.00247

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00195

Hom.:

Bravo

AF:

0.00127

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00311

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00302

AC:

ExAC

AF:

0.00128

AC:

155

EpiCase

AF:

0.00240

EpiControl

AF:

0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant

Benign:3Other:1

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Likely benign and reported on 07-24-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

not specified

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 15, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 25, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 18, 2023	The c.19135C>T (p.R6379C) alteration is located in exon 106 (coding exon 105) of the SYNE2 gene. This alteration results from a C to T substitution at nucleotide position 19135, causing the arginine (R) at amino acid position 6379 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SYNE2: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

SYNE2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 07, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.61

DEOGEN2

Benign

0.096

.;T;T;T;T;.;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.87

D;D;D;D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.015

T;T;T;T;T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

0.90

L;.;L;.;.;.;.

PrimateAI

Benign

0.27

PROVEAN

Pathogenic

-4.4

D;.;D;D;D;.;D

REVEL

Benign

0.083

Sift

Uncertain

0.024

D;.;D;D;D;.;D

Sift4G

Uncertain

0.0050

D;D;D;D;D;.;D

Polyphen

0.99

D;.;D;B;.;.;D

Vest4

0.28

MVP

0.52

MPC

0.063

ClinPred

0.067

GERP RS

3.5

Varity_R

0.13

gMVP

0.14

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