rs11629287

chr14-64146127-C-T

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.15543C>T(p.Ile5181=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 1,600,702 control chromosomes in the GnomAD database, including 99,823 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I5181I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.40 (12615 hom., cov: 33)
  • Exomes 𝑓: 0.34 (87208 hom.)
• Consequence: SYNE2 NM_182914.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.18

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=-0.54).
• BP6: Variant 14-64146127-C-T is Benign according to our data. Variant chr14-64146127-C-T is described in ClinVar as [Benign]. Clinvar id is 130479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64146127-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.18 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.15543C>T	p.Ile5181=	synonymous_variant	84/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.15543C>T	p.Ile5181=	synonymous_variant	84/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.399 AC: 60575 AN: 151854 Hom.: 12584 Cov.: 33

Gnomad AFR AF: 0.527

Gnomad AMI AF: 0.332

Gnomad AMR AF: 0.364

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.511

Gnomad SAS AF: 0.330

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.386

GnomAD3 exomes AF: 0.367 AC: 90778 AN: 247578 Hom.: 17280 AF XY: 0.359 AC XY: 48051 AN XY: 133918

Gnomad AFR exome AF: 0.540

Gnomad AMR exome AF: 0.385

Gnomad ASJ exome AF: 0.389

Gnomad EAS exome AF: 0.514

Gnomad SAS exome AF: 0.325

Gnomad FIN exome AF: 0.348

Gnomad NFE exome AF: 0.327

Gnomad OTH exome AF: 0.342

GnomAD4 exome AF: 0.343 AC: 496430 AN: 1448730 Hom.: 87208 Cov.: 30 AF XY: 0.342 AC XY: 246400 AN XY: 721256

Gnomad4 AFR exome AF: 0.536

Gnomad4 AMR exome AF: 0.382

Gnomad4 ASJ exome AF: 0.382

Gnomad4 EAS exome AF: 0.498

Gnomad4 SAS exome AF: 0.326

Gnomad4 FIN exome AF: 0.349

Gnomad4 NFE exome AF: 0.329

Gnomad4 OTH exome AF: 0.358

GnomAD4 genome AF: 0.399 AC: 60662 AN: 151972 Hom.: 12615 Cov.: 33 AF XY: 0.398 AC XY: 29583 AN XY: 74286

Gnomad4 AFR AF: 0.528

Gnomad4 AMR AF: 0.364

Gnomad4 ASJ AF: 0.389

Gnomad4 EAS AF: 0.511

Gnomad4 SAS AF: 0.330

Gnomad4 FIN AF: 0.360

Gnomad4 NFE AF: 0.333

Gnomad4 OTH AF: 0.387

Alfa AF: 0.348 Hom.: 11969

Bravo AF: 0.409

Asia WGS AF: 0.418 AC: 1449 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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	Jan 31, 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
Cadd	Benign	1.6
Dann	Benign	0.59

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: rs11629287; hg19: chr14-64612845; COSMIC: COSV59972358;