rs34944385

chr14-64122119-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_182914.3(SYNE2):c.13266G>A(p.Gln4422=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0151 in 1,613,886 control chromosomes in the GnomAD database, including 208 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (20 hom., cov: 32)
  • Exomes 𝑓: 0.015 (188 hom.)
• Consequence: SYNE2 NM_182914.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.15

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=-0.53).
• BP6: Variant 14-64122119-G-A is Benign according to our data. Variant chr14-64122119-G-A is described in ClinVar as [Benign]. Clinvar id is 130471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64122119-G-A is described in Lovd as [Benign]. Variant chr14-64122119-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.15 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0126 (1923/152254) while in subpopulation SAS AF= 0.0224 (108/4826). AF 95% confidence interval is 0.019. There are 20 homozygotes in gnomad4. There are 1029 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1920 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.13266G>A	p.Gln4422=	synonymous_variant	69/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.13266G>A	p.Gln4422=	synonymous_variant	69/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1920 AN: 152136 Hom.: 20 Cov.: 32

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0224

Gnomad FIN AF: 0.0282

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0151

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0139 AC: 3496 AN: 251208 Hom.: 29 AF XY: 0.0150 AC XY: 2034 AN XY: 135778

Gnomad AFR exome AF: 0.00265

Gnomad AMR exome AF: 0.00552

Gnomad ASJ exome AF: 0.0179

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0221

Gnomad FIN exome AF: 0.0253

Gnomad NFE exome AF: 0.0153

Gnomad OTH exome AF: 0.0173

GnomAD4 exome AF: 0.0153 AC: 22388 AN: 1461632 Hom.: 188 Cov.: 32 AF XY: 0.0155 AC XY: 11302 AN XY: 727124

Gnomad4 AFR exome AF: 0.00248

Gnomad4 AMR exome AF: 0.00593

Gnomad4 ASJ exome AF: 0.0184

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0215

Gnomad4 FIN exome AF: 0.0257

Gnomad4 NFE exome AF: 0.0155

Gnomad4 OTH exome AF: 0.0166

GnomAD4 genome AF: 0.0126 AC: 1923 AN: 152254 Hom.: 20 Cov.: 32 AF XY: 0.0138 AC XY: 1029 AN XY: 74448

Gnomad4 AFR AF: 0.00291

Gnomad4 AMR AF: 0.0154

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0224

Gnomad4 FIN AF: 0.0282

Gnomad4 NFE AF: 0.0151

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0135 Hom.: 11

Bravo AF: 0.0106

Asia WGS AF: 0.0170 AC: 58 AN: 3478

EpiCase AF: 0.0159

EpiControl AF: 0.0133

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 26, 2020	- -
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. -

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
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. -

SYNE2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 03, 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	-0.53
Cadd	Benign	2.2
Dann	Benign	0.84

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: rs34944385; hg19: chr14-64588837;