chr14-64093374-G-A

Position:

chr14-64093374-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBA1

The NM_182914.3(SYNE2):c.12002G>A(p.Trp4001Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0722 in 1,612,338 control chromosomes in the GnomAD database, including 5,029 homozygotes. Variant has been reported in ClinVar as Benign (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.089 ( 670 hom., cov: 32)

Exomes 𝑓: 0.070 ( 4359 hom. )

Consequence

SYNE2
NM_182914.3 stop_gained

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.36

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 -8 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

BP6

Variant 14-64093374-G-A is Benign according to our data. Variant chr14-64093374-G-A is described in ClinVar as [Benign]. Clinvar id is 130463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64093374-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3 linkuse as main transcript	c.12002G>A	p.Trp4001Ter	stop_gained	61/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6 linkuse as main transcript	c.12002G>A	p.Trp4001Ter	stop_gained	61/116	1	NM_182914.3	P4	Q8WXH0-2

Frequencies

GnomAD3 genomes

AF:

0.0889

AC:

13508

AN:

152024

Hom.:

669

Cov.:

show subpopulations

Gnomad AFR

AF:

0.130

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0793

Gnomad ASJ

AF:

0.172

Gnomad EAS

AF:

0.109

Gnomad SAS

AF:

0.143

Gnomad FIN

AF:

0.0570

Gnomad MID

AF:

0.111

Gnomad NFE

AF:

0.0623

Gnomad OTH

AF:

0.0957

GnomAD3 exomes

AF:

0.0853

AC:

21442

AN:

251362

Hom.:

1136

AF XY:

0.0874

AC XY:

11871

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.131

Gnomad AMR exome

AF:

0.0484

Gnomad ASJ exome

AF:

0.181

Gnomad EAS exome

AF:

0.116

Gnomad SAS exome

AF:

0.142

Gnomad FIN exome

AF:

0.0583

Gnomad NFE exome

AF:

0.0658

Gnomad OTH exome

AF:

0.0987

GnomAD4 exome

AF:

0.0704

AC:

102859

AN:

1460196

Hom.:

4359

Cov.:

AF XY:

0.0729

AC XY:

52954

AN XY:

726480

show subpopulations

Gnomad4 AFR exome

AF:

0.134

Gnomad4 AMR exome

AF:

0.0521

Gnomad4 ASJ exome

AF:

0.185

Gnomad4 EAS exome

AF:

0.114

Gnomad4 SAS exome

AF:

0.137

Gnomad4 FIN exome

AF:

0.0588

Gnomad4 NFE exome

AF:

0.0594

Gnomad4 OTH exome

AF:

0.0861

GnomAD4 genome

AF:

0.0888

AC:

13514

AN:

152142

Hom.:

670

Cov.:

AF XY:

0.0904

AC XY:

6723

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.130

Gnomad4 AMR

AF:

0.0792

Gnomad4 ASJ

AF:

0.172

Gnomad4 EAS

AF:

0.109

Gnomad4 SAS

AF:

0.142

Gnomad4 FIN

AF:

0.0570

Gnomad4 NFE

AF:

0.0623

Gnomad4 OTH

AF:

0.0947

Alfa

AF:

0.0751

Hom.:

731

Bravo

AF:

0.0904

TwinsUK

AF:

0.0569

AC:

211

ALSPAC

AF:

0.0633

AC:

244

ESP6500AA

AF:

0.115

AC:

505

ESP6500EA

AF:

0.0572

AC:

492

ExAC

AF:

0.0868

AC:

10535

Asia WGS

AF:

0.114

AC:

397

AN:

3478

EpiCase

AF:

0.0695

EpiControl

AF:

0.0743

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 12, 2015	- -
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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 25854761) -

Emery-Dreifuss muscular dystrophy 5, autosomal dominant

Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.080

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Uncertain

0.98

Eigen

Uncertain

0.39

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.80

MutationTaster

Benign

1.0e-37

P;P;P;P;P;P;P

Vest4

0.75

GERP RS

1.9

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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