rs35203186

Positions:

chr14-64070780-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000555002.6(SYNE2):c.10567A>C(p.Lys3523Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0194 in 1,614,150 control chromosomes in the GnomAD database, including 496 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 (★★).

Frequency

Genomes: 𝑓 0.030 ( 119 hom., cov: 33)

Exomes 𝑓: 0.018 ( 377 hom. )

Consequence

SYNE2
ENST00000555002.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.135

Variant links:

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]

SYNE2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016273856).

BP6

Variant 14-64070780-A-C is Benign according to our data. Variant chr14-64070780-A-C is described in ClinVar as [Benign]. Clinvar id is 130456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64070780-A-C is described in Lovd as [Likely_benign]. Variant chr14-64070780-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0675 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE2	NM_182914.3 linkuse as main transcript	c.10567A>C	p.Lys3523Gln	missense_variant	52/116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6 linkuse as main transcript	c.10567A>C	p.Lys3523Gln	missense_variant	52/116	1	NM_182914.3	ENSP00000450831	P4	Q8WXH0-2

Frequencies

GnomAD3 genomes

AF:

0.0303

AC:

4606

AN:

152178

Hom.:

118

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0535

Gnomad AMI

AF:

0.0462

Gnomad AMR

AF:

0.0166

Gnomad ASJ

AF:

0.00922

Gnomad EAS

AF:

0.0734

Gnomad SAS

AF:

0.00621

Gnomad FIN

AF:

0.0489

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0155

Gnomad OTH

AF:

0.0339

GnomAD3 exomes

AF:

0.0242

AC:

6041

AN:

249522

Hom.:

117

AF XY:

0.0230

AC XY:

3113

AN XY:

135372

show subpopulations

Gnomad AFR exome

AF:

0.0563

Gnomad AMR exome

AF:

0.0124

Gnomad ASJ exome

AF:

0.00705

Gnomad EAS exome

AF:

0.0824

Gnomad SAS exome

AF:

0.00539

Gnomad FIN exome

AF:

0.0466

Gnomad NFE exome

AF:

0.0167

Gnomad OTH exome

AF:

0.0205

GnomAD4 exome

AF:

0.0182

AC:

26649

AN:

1461854

Hom.:

377

Cov.:

AF XY:

0.0176

AC XY:

12827

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.0564

Gnomad4 AMR exome

AF:

0.0139

Gnomad4 ASJ exome

AF:

0.00716

Gnomad4 EAS exome

AF:

0.0600

Gnomad4 SAS exome

AF:

0.00425

Gnomad4 FIN exome

AF:

0.0447

Gnomad4 NFE exome

AF:

0.0157

Gnomad4 OTH exome

AF:

0.0206

GnomAD4 genome

AF:

0.0303

AC:

4619

AN:

152296

Hom.:

119

Cov.:

AF XY:

0.0316

AC XY:

2355

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0537

Gnomad4 AMR

AF:

0.0166

Gnomad4 ASJ

AF:

0.00922

Gnomad4 EAS

AF:

0.0736

Gnomad4 SAS

AF:

0.00601

Gnomad4 FIN

AF:

0.0489

Gnomad4 NFE

AF:

0.0154

Gnomad4 OTH

AF:

0.0331

Alfa

AF:

0.0212

Hom.:

Bravo

AF:

0.0309

TwinsUK

AF:

0.0156

AC:

ALSPAC

AF:

0.0163

AC:

ESP6500AA

AF:

0.0523

AC:

199

ESP6500EA

AF:

0.0146

AC:

120

ExAC

AF:

0.0243

AC:

2934

Asia WGS

AF:

0.0390

AC:

136

AN:

3478

EpiCase

AF:

0.0203

EpiControl

AF:

0.0202

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 10, 2020	- -

Emery-Dreifuss muscular dystrophy 5, autosomal dominant

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.57

CADD

Benign

1.6

DANN

Benign

0.60

DEOGEN2

Benign

0.0057

.;T;T;T;T

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.083

LIST_S2

Benign

0.80

T;T;T;T;T

MetaRNN

Benign

0.0016

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

L;.;L;.;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.090

N;.;N;N;N

REVEL

Benign

0.022

Sift

Benign

0.62

T;.;T;T;T

Sift4G

Benign

0.13

T;T;T;T;T

Polyphen

0.010

B;.;B;.;.

Vest4

0.18

MPC

0.051

ClinPred

0.00087

GERP RS

0.15

Varity_R

0.034

gMVP

0.096

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over