rs2781377

chr14-64093374-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 8P and 16B. PVS1 BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.36

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]

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]

ACMG classification

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	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	c.12002G>A	p.Trp4001Ter	stop_gained	61/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.0889 AC: 13508 AN: 152024 Hom.: 669 Cov.: 32

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

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.: 32 AF XY: 0.0729 AC XY: 52954 AN XY: 726480

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.: 32 AF XY: 0.0904 AC XY: 6723 AN XY: 74378

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 12, 2015	- -

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

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

This variant is associated with the following publications: (PMID: 25854761) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Pathogenic	0.46
Cadd	Pathogenic	36
Dann	Uncertain	0.98
Eigen	Uncertain	0.39
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.80	D
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

Other links and lift over

dbSNP: rs2781377; hg19: chr14-64560092; COSMIC: COSV59963005; COSMIC: COSV59963005;