rs200437377

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000555002.6(SYNE2):c.3506G>A(p.Arg1169His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000949 in 1,613,294 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1169C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00099 ( 1 hom. )

Consequence

SYNE2
ENST00000555002.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 0.167

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.036743402).

BP6

Variant 14-64000587-G-A is Benign according to our data. Variant chr14-64000587-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282514.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=2, Uncertain_significance=3}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000532 (81/152212) while in subpopulation NFE AF= 0.000926 (63/68012). AF 95% confidence interval is 0.000742. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 81 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE2	NM_182914.3 linkuse as main transcript	c.3506G>A	p.Arg1169His	missense_variant	28/116	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.3506G>A	p.Arg1169His	missense_variant	28/116	1	NM_182914.3	ENSP00000450831	P4	Q8WXH0-2

Frequencies

GnomAD3 genomes

AF:

0.000533

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000926

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000494

AC:

123

AN:

249150

Hom.:

AF XY:

0.000525

AC XY:

AN XY:

135198

show subpopulations

Gnomad AFR exome

AF:

0.000452

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000920

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000992

AC:

1450

AN:

1461082

Hom.:

Cov.:

AF XY:

0.000985

AC XY:

716

AN XY:

726856

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000169

Gnomad4 NFE exome

AF:

0.00122

Gnomad4 OTH exome

AF:

0.000812

GnomAD4 genome

AF:

0.000532

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.000926

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000913

Hom.:

Bravo

AF:

0.000521

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000556

AC:

ESP6500EA

AF:

0.00111

AC:

ExAC

AF:

0.000422

AC:

EpiCase

AF:

0.00115

EpiControl

AF:

0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 19, 2023	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 12, 2023	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 25, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 16, 2024	The c.3506G>A (p.R1169H) alteration is located in exon 28 (coding exon 27) of the SYNE2 gene. This alteration results from a G to A substitution at nucleotide position 3506, causing the arginine (R) at amino acid position 1169 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 07, 2015

- -

SYNE2-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 10, 2023

This variant is classified as likely 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

0.074

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.62

CADD

Benign

6.7

DANN

Benign

0.26

DEOGEN2

Benign

0.0088

.;T;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.20

T;T;T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.037

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

N;.;N;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.10

N;.;N;N

REVEL

Benign

0.027

Sift

Benign

0.51

T;.;T;T

Sift4G

Benign

0.59

T;T;T;T

Polyphen

0.0

B;.;B;.

Vest4

0.17

MVP

0.36

MPC

0.055

ClinPred

0.0015

GERP RS

-1.6

Varity_R

0.021

gMVP

0.062

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