rs10151658

chr14-64146140-C-Achr14-64146140-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182914.3(SYNE2):c.15556C>A(p.Leu5186Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.461 in 1,605,976 control chromosomes in the GnomAD database, including 179,639 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L5186T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.57 (27007 hom., cov: 32)
  • Exomes 𝑓: 0.45 (152632 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.568

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.1527055E-7).
• BP6: Variant 14-64146140-C-A is Benign according to our data. Variant chr14-64146140-C-A is described in ClinVar as [Benign]. Clinvar id is 130480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64146140-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.845 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.15556C>A	p.Leu5186Met	missense_variant	84/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.15556C>A	p.Leu5186Met	missense_variant	84/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.567 AC: 86206 AN: 151934 Hom.: 26951 Cov.: 32

Gnomad AFR AF: 0.852

Gnomad AMI AF: 0.502

Gnomad AMR AF: 0.498

Gnomad ASJ AF: 0.582

Gnomad EAS AF: 0.649

Gnomad SAS AF: 0.508

Gnomad FIN AF: 0.437

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.429

Gnomad OTH AF: 0.549

GnomAD3 exomes AF: 0.497 AC: 123574 AN: 248594 Hom.: 32566 AF XY: 0.489 AC XY: 65692 AN XY: 134432

Gnomad AFR exome AF: 0.866

Gnomad AMR exome AF: 0.482

Gnomad ASJ exome AF: 0.591

Gnomad EAS exome AF: 0.656

Gnomad SAS exome AF: 0.505

Gnomad FIN exome AF: 0.424

Gnomad NFE exome AF: 0.428

Gnomad OTH exome AF: 0.479

GnomAD4 exome AF: 0.450 AC: 654218 AN: 1453924 Hom.: 152632 Cov.: 31 AF XY: 0.451 AC XY: 326293 AN XY: 723444

Gnomad4 AFR exome AF: 0.872

Gnomad4 AMR exome AF: 0.484

Gnomad4 ASJ exome AF: 0.581

Gnomad4 EAS exome AF: 0.611

Gnomad4 SAS exome AF: 0.503

Gnomad4 FIN exome AF: 0.423

Gnomad4 NFE exome AF: 0.422

Gnomad4 OTH exome AF: 0.489

GnomAD4 genome AF: 0.568 AC: 86315 AN: 152052 Hom.: 27007 Cov.: 32 AF XY: 0.566 AC XY: 42029 AN XY: 74310

Gnomad4 AFR AF: 0.853

Gnomad4 AMR AF: 0.498

Gnomad4 ASJ AF: 0.582

Gnomad4 EAS AF: 0.649

Gnomad4 SAS AF: 0.508

Gnomad4 FIN AF: 0.437

Gnomad4 NFE AF: 0.429

Gnomad4 OTH AF: 0.549

Alfa AF: 0.460 Hom.: 25491

Bravo AF: 0.586

TwinsUK AF: 0.415 AC: 1540

ALSPAC AF: 0.404 AC: 1557

ESP6500AA AF: 0.850 AC: 3745

ESP6500EA AF: 0.438 AC: 3771

ExAC AF: 0.502 AC: 60915

Asia WGS AF: 0.575 AC: 1996 AN: 3476

EpiCase AF: 0.428

EpiControl AF: 0.435

ClinVar

Significance: Benign

Submissions summary: Benign:8

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

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	1.9
Dann	Benign	0.52
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.084	T;T;T;T;T
MetaRNN	Benign	6.2e-7	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.32	N;.;N;.;.
MutationTaster	Benign	2.5e-14	P;P;P;P;P;P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.090	N;.;N;N;N
REVEL	Benign	0.020
Sift	Benign	0.72	T;.;T;T;T
Sift4G	Benign	0.74	T;T;T;T;T
Polyphen		0.0060	B;.;B;B;.
Vest4		0.15
MPC		0.050
ClinPred		0.0024	T
GERP RS		-2.1
Varity_R		0.032
gMVP		0.16

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: rs10151658; hg19: chr14-64612858; COSMIC: COSV59972370;