14-64087799-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_182914.3(SYNE2):c.11613A>G(p.Val3871=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0762 in 1,613,930 control chromosomes in the GnomAD database, including 5,365 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (992 hom., cov: 32)
  • Exomes 𝑓: 0.073 (4373 hom.)
• Consequence: SYNE2 NM_182914.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.543

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 14-64087799-A-G is Benign according to our data. Variant chr14-64087799-A-G is described in ClinVar as [Benign]. Clinvar id is 130459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64087799-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.543 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.11613A>G	p.Val3871=	synonymous_variant	58/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.11613A>G	p.Val3871=	synonymous_variant	58/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15941 AN: 152154 Hom.: 984 Cov.: 32

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.112

Gnomad ASJ AF: 0.0844

Gnomad EAS AF: 0.0504

Gnomad SAS AF: 0.0617

Gnomad FIN AF: 0.0869

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0741

Gnomad OTH AF: 0.0973

GnomAD3 exomes AF: 0.0832 AC: 20879 AN: 250920 Hom.: 1028 AF XY: 0.0798 AC XY: 10831 AN XY: 135790

Gnomad AFR exome AF: 0.168

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.0846

Gnomad EAS exome AF: 0.0492

Gnomad SAS exome AF: 0.0607

Gnomad FIN exome AF: 0.0798

Gnomad NFE exome AF: 0.0728

Gnomad OTH exome AF: 0.0866

GnomAD4 exome AF: 0.0732 AC: 106938 AN: 1461658 Hom.: 4373 Cov.: 32 AF XY: 0.0726 AC XY: 52813 AN XY: 727118

Gnomad4 AFR exome AF: 0.180

Gnomad4 AMR exome AF: 0.118

Gnomad4 ASJ exome AF: 0.0794

Gnomad4 EAS exome AF: 0.0529

Gnomad4 SAS exome AF: 0.0595

Gnomad4 FIN exome AF: 0.0759

Gnomad4 NFE exome AF: 0.0693

Gnomad4 OTH exome AF: 0.0781

GnomAD4 genome AF: 0.105 AC: 15997 AN: 152272 Hom.: 992 Cov.: 32 AF XY: 0.105 AC XY: 7838 AN XY: 74448

Gnomad4 AFR AF: 0.172

Gnomad4 AMR AF: 0.112

Gnomad4 ASJ AF: 0.0844

Gnomad4 EAS AF: 0.0503

Gnomad4 SAS AF: 0.0619

Gnomad4 FIN AF: 0.0869

Gnomad4 NFE AF: 0.0741

Gnomad4 OTH AF: 0.0991

Alfa AF: 0.0798 Hom.: 1055

Bravo AF: 0.109

Asia WGS AF: 0.0860 AC: 298 AN: 3478

EpiCase AF: 0.0684

EpiControl AF: 0.0717

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 15, 2013

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

SYNE2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 05, 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	-0.80
Cadd	Benign	1.9
Dann	Benign	0.67

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

Other links and lift over

dbSNP: rs17101637; hg19: chr14-64554517;