rs2256191

Positions:

• chr14-64190137-T-C

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.17938T>C​(p.Leu5980=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 1,613,720 control chromosomes in the GnomAD database, including 119,799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (18869 hom., cov: 31)
  • Exomes 𝑓: 0.36 (100930 hom.)
• Consequence: SYNE2 NM_182914.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.100

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=-0.57).
• BP6: Variant 14-64190137-T-C is Benign according to our data. Variant chr14-64190137-T-C is described in ClinVar as [Benign]. Clinvar id is 130488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64190137-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.739 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.17938T>C	p.Leu5980=	synonymous_variant	99/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.17938T>C	p.Leu5980=	synonymous_variant	99/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70641 AN: 151804 Hom.: 18831 Cov.: 31

Gnomad AFR AF: 0.745

Gnomad AMI AF: 0.375

Gnomad AMR AF: 0.389

Gnomad ASJ AF: 0.494

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.396

Gnomad FIN AF: 0.274

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.354

Gnomad OTH AF: 0.463

GnomAD3 exomes AF: 0.388 AC: 97453 AN: 251396 Hom.: 20423 AF XY: 0.382 AC XY: 51923 AN XY: 135876

Gnomad AFR exome AF: 0.754

Gnomad AMR exome AF: 0.357

Gnomad ASJ exome AF: 0.492

Gnomad EAS exome AF: 0.383

Gnomad SAS exome AF: 0.392

Gnomad FIN exome AF: 0.286

Gnomad NFE exome AF: 0.355

Gnomad OTH exome AF: 0.371

GnomAD4 exome AF: 0.364 AC: 531648 AN: 1461796 Hom.: 100930 Cov.: 47 AF XY: 0.364 AC XY: 264385 AN XY: 727206

Gnomad4 AFR exome AF: 0.758

Gnomad4 AMR exome AF: 0.360

Gnomad4 ASJ exome AF: 0.491

Gnomad4 EAS exome AF: 0.356

Gnomad4 SAS exome AF: 0.393

Gnomad4 FIN exome AF: 0.284

Gnomad4 NFE exome AF: 0.349

Gnomad4 OTH exome AF: 0.391

GnomAD4 genome AF: 0.466 AC: 70728 AN: 151924 Hom.: 18869 Cov.: 31 AF XY: 0.458 AC XY: 34003 AN XY: 74250

Gnomad4 AFR AF: 0.746

Gnomad4 AMR AF: 0.388

Gnomad4 ASJ AF: 0.494

Gnomad4 EAS AF: 0.369

Gnomad4 SAS AF: 0.396

Gnomad4 FIN AF: 0.274

Gnomad4 NFE AF: 0.354

Gnomad4 OTH AF: 0.457

Alfa AF: 0.388 Hom.: 28018

Bravo AF: 0.487

Asia WGS AF: 0.384 AC: 1334 AN: 3478

EpiCase AF: 0.369

EpiControl AF: 0.376

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Benign:4

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	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 28, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.30
DANN	Benign	0.53

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: rs2256191; hg19: chr14-64656855; COSMIC: COSV59943958;