14-64052317-A-G

Position:

chr14-64052317-A-G

Variant summary

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

The NM_182914.3(SYNE2):c.8404A>G(p.Ser2802Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.927 in 1,614,086 control chromosomes in the GnomAD database, including 694,149 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. S2802N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.91 ( 63034 hom., cov: 32)

Exomes 𝑓: 0.93 ( 631115 hom. )

Consequence

SYNE2
NM_182914.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.59

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=9.721277E-7).

BP6

Variant 14-64052317-A-G is Benign according to our data. Variant chr14-64052317-A-G is described in ClinVar as [Benign]. Clinvar id is 130513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64052317-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.934 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3 linkuse as main transcript	c.8404A>G	p.Ser2802Gly	missense_variant	48/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6 linkuse as main transcript	c.8404A>G	p.Ser2802Gly	missense_variant	48/116	1	NM_182914.3	P4	Q8WXH0-2

Frequencies

GnomAD3 genomes

AF:

0.909

AC:

138301

AN:

152120

Hom.:

62983

Cov.:

show subpopulations

Gnomad AFR

AF:

0.868

Gnomad AMI

AF:

0.995

Gnomad AMR

AF:

0.918

Gnomad ASJ

AF:

0.827

Gnomad EAS

AF:

0.860

Gnomad SAS

AF:

0.814

Gnomad FIN

AF:

0.943

Gnomad MID

AF:

0.889

Gnomad NFE

AF:

0.940

Gnomad OTH

AF:

0.904

GnomAD3 exomes

AF:

0.908

AC:

226629

AN:

249470

Hom.:

103293

AF XY:

0.905

AC XY:

122458

AN XY:

135348

show subpopulations

Gnomad AFR exome

AF:

0.868

Gnomad AMR exome

AF:

0.951

Gnomad ASJ exome

AF:

0.820

Gnomad EAS exome

AF:

0.844

Gnomad SAS exome

AF:

0.822

Gnomad FIN exome

AF:

0.943

Gnomad NFE exome

AF:

0.937

Gnomad OTH exome

AF:

0.899

GnomAD4 exome

AF:

0.928

AC:

1357122

AN:

1461848

Hom.:

631115

Cov.:

AF XY:

0.925

AC XY:

672636

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.864

Gnomad4 AMR exome

AF:

0.947

Gnomad4 ASJ exome

AF:

0.815

Gnomad4 EAS exome

AF:

0.867

Gnomad4 SAS exome

AF:

0.827

Gnomad4 FIN exome

AF:

0.942

Gnomad4 NFE exome

AF:

0.943

Gnomad4 OTH exome

AF:

0.910

GnomAD4 genome

AF:

0.909

AC:

138411

AN:

152238

Hom.:

63034

Cov.:

AF XY:

0.907

AC XY:

67524

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.869

Gnomad4 AMR

AF:

0.918

Gnomad4 ASJ

AF:

0.827

Gnomad4 EAS

AF:

0.860

Gnomad4 SAS

AF:

0.814

Gnomad4 FIN

AF:

0.943

Gnomad4 NFE

AF:

0.940

Gnomad4 OTH

AF:

0.903

Alfa

AF:

0.925

Hom.:

155777

Bravo

AF:

0.909

TwinsUK

AF:

0.943

AC:

3497

ALSPAC

AF:

0.937

AC:

3611

ESP6500AA

AF:

0.870

AC:

3264

ESP6500EA

AF:

0.932

AC:

7643

ExAC

AF:

0.907

AC:

109514

Asia WGS

AF:

0.844

AC:

2935

AN:

3478

EpiCase

AF:

0.933

EpiControl

AF:

0.929

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant

Benign:4

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

not specified

Benign:2

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

not provided

Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.016

DANN

Benign

0.60

DEOGEN2

Benign

0.031

.;T;T;T

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.37

T;T;T;T

MetaRNN

Benign

9.7e-7

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;.;L;.

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.7

N;.;N;N

REVEL

Benign

0.022

Sift

Benign

0.36

T;.;T;T

Sift4G

Benign

0.061

T;T;T;T

Polyphen

0.058

B;.;B;.

Vest4

0.028

MPC

0.053

ClinPred

0.0057

GERP RS

-6.9

Varity_R

0.034

gMVP

0.059

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