rs189611387

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PP3_ModerateBP6_Very_StrongBS1BS2

The NM_182914.3(SYNE2):c.18039-5T>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,614,132 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 7 hom. )

Consequence

SYNE2
NM_182914.3 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.9997

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.923

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 -14 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

BP6

Variant 14-64202796-T-A is Benign according to our data. Variant chr14-64202796-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 193771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64202796-T-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00198 (301/152254) while in subpopulation NFE AF= 0.00318 (216/68010). AF 95% confidence interval is 0.00283. There are 2 homozygotes in gnomad4. There are 128 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 301 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3 linkuse as main transcript	c.18039-5T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6 linkuse as main transcript	c.18039-5T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_182914.3	P4	Q8WXH0-2

Frequencies

GnomAD3 genomes

AF:

0.00198

AC:

301

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00605

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00318

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00235

AC:

590

AN:

251462

Hom.:

AF XY:

0.00226

AC XY:

307

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.00283

Gnomad ASJ exome

AF:

0.00595

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00131

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00316

Gnomad OTH exome

AF:

0.00212

GnomAD4 exome

AF:

0.00302

AC:

4419

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00303

AC XY:

2206

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.000538

Gnomad4 AMR exome

AF:

0.00259

Gnomad4 ASJ exome

AF:

0.00566

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000951

Gnomad4 FIN exome

AF:

0.000431

Gnomad4 NFE exome

AF:

0.00337

Gnomad4 OTH exome

AF:

0.00329

GnomAD4 genome

AF:

0.00198

AC:

301

AN:

152254

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

128

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.00203

Gnomad4 ASJ

AF:

0.00605

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00318

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00228

Hom.:

Bravo

AF:

0.00231

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00349

EpiControl

AF:

0.00480

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 28, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	SYNE2: BS1, BS2 -

Emery-Dreifuss muscular dystrophy 5, autosomal dominant

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 10, 2015

- -

SYNE2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 2019

This variant is classified as 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

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Benign

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.40

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.40

Position offset: 5

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