rs11847087

chr14-64053302-A-G

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.9389A>G(p.Asn3130Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0427 in 1,608,316 control chromosomes in the GnomAD database, including 2,162 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (585 hom., cov: 33)
  • Exomes 𝑓: 0.040 (1577 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.891

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013741553).
• BP6: Variant 14-64053302-A-G is Benign according to our data. Variant chr14-64053302-A-G is described in ClinVar as [Benign]. Clinvar id is 130519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64053302-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.151 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.9389A>G	p.Asn3130Ser	missense_variant	48/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.9389A>G	p.Asn3130Ser	missense_variant	48/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.0699 AC: 10642 AN: 152158 Hom.: 577 Cov.: 33

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.0451

Gnomad ASJ AF: 0.0631

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00828

Gnomad FIN AF: 0.0267

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0406

Gnomad OTH AF: 0.0641

GnomAD3 exomes AF: 0.0404 AC: 9861 AN: 244102 Hom.: 347 AF XY: 0.0381 AC XY: 5035 AN XY: 132230

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.0305

Gnomad ASJ exome AF: 0.0659

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00864

Gnomad FIN exome AF: 0.0283

Gnomad NFE exome AF: 0.0423

Gnomad OTH exome AF: 0.0494

GnomAD4 exome AF: 0.0399 AC: 58062 AN: 1456040 Hom.: 1577 Cov.: 37 AF XY: 0.0389 AC XY: 28155 AN XY: 723852

Gnomad4 AFR exome AF: 0.161

Gnomad4 AMR exome AF: 0.0328

Gnomad4 ASJ exome AF: 0.0613

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00890

Gnomad4 FIN exome AF: 0.0256

Gnomad4 NFE exome AF: 0.0401

Gnomad4 OTH exome AF: 0.0450

GnomAD4 genome AF: 0.0701 AC: 10673 AN: 152276 Hom.: 585 Cov.: 33 AF XY: 0.0687 AC XY: 5113 AN XY: 74454

Gnomad4 AFR AF: 0.154

Gnomad4 AMR AF: 0.0450

Gnomad4 ASJ AF: 0.0631

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00829

Gnomad4 FIN AF: 0.0267

Gnomad4 NFE AF: 0.0406

Gnomad4 OTH AF: 0.0639

Alfa AF: 0.0478 Hom.: 546

Bravo AF: 0.0759

TwinsUK AF: 0.0369 AC: 137

ALSPAC AF: 0.0420 AC: 162

ESP6500AA AF: 0.144 AC: 522

ESP6500EA AF: 0.0406 AC: 330

ExAC AF: 0.0418 AC: 5043

Asia WGS AF: 0.0180 AC: 64 AN: 3478

EpiCase AF: 0.0429

EpiControl AF: 0.0439

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	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. -

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 14, 2018

- -

SYNE2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 20, 2020

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
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	6.8
Dann	Uncertain	0.98
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.78	T;T;T;T
MetaRNN	Benign	0.0014	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;.;M;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	N;.;N;N
REVEL	Benign	0.031
Sift	Benign	0.21	T;.;T;T
Sift4G	Benign	0.21	T;T;T;T
Polyphen		0.021	B;.;B;.
Vest4		0.13
MPC		0.043
ClinPred		0.0097	T
GERP RS		3.0
Varity_R		0.029
gMVP		0.15

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: rs11847087; hg19: chr14-64520020;