rs17751301

Positions:

chr14-64003110-C-T

Variant summary

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

The NM_182914.3(SYNE2):c.4177C>T(p.Arg1393Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0649 in 1,614,050 control chromosomes in the GnomAD database, including 3,992 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. R1393Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.049 ( 243 hom., cov: 32)

Exomes 𝑓: 0.067 ( 3749 hom. )

Consequence

SYNE2
NM_182914.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.03

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=0.0018231869).

BP6

Variant 14-64003110-C-T is Benign according to our data. Variant chr14-64003110-C-T is described in ClinVar as [Benign]. Clinvar id is 130497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64003110-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0792 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.4177C>T	p.Arg1393Trp	missense_variant	30/116	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.4177C>T	p.Arg1393Trp	missense_variant	30/116	1	NM_182914.3	ENSP00000450831	P4	Q8WXH0-2

Frequencies

GnomAD3 genomes

AF:

0.0487

AC:

7404

AN:

152156

Hom.:

245

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0118

Gnomad AMI

AF:

0.0285

Gnomad AMR

AF:

0.0833

Gnomad ASJ

AF:

0.0545

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0207

Gnomad FIN

AF:

0.0373

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0712

Gnomad OTH

AF:

0.0397

GnomAD3 exomes

AF:

0.0602

AC:

14960

AN:

248510

Hom.:

663

AF XY:

0.0571

AC XY:

7700

AN XY:

134846

show subpopulations

Gnomad AFR exome

AF:

0.0123

Gnomad AMR exome

AF:

0.131

Gnomad ASJ exome

AF:

0.0511

Gnomad EAS exome

AF:

0.000223

Gnomad SAS exome

AF:

0.0202

Gnomad FIN exome

AF:

0.0424

Gnomad NFE exome

AF:

0.0698

Gnomad OTH exome

AF:

0.0603

GnomAD4 exome

AF:

0.0666

AC:

97319

AN:

1461776

Hom.:

3749

Cov.:

AF XY:

0.0648

AC XY:

47126

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.0102

Gnomad4 AMR exome

AF:

0.124

Gnomad4 ASJ exome

AF:

0.0523

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0207

Gnomad4 FIN exome

AF:

0.0424

Gnomad4 NFE exome

AF:

0.0742

Gnomad4 OTH exome

AF:

0.0558

GnomAD4 genome

AF:

0.0486

AC:

7398

AN:

152274

Hom.:

243

Cov.:

AF XY:

0.0469

AC XY:

3489

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0117

Gnomad4 AMR

AF:

0.0830

Gnomad4 ASJ

AF:

0.0545

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0205

Gnomad4 FIN

AF:

0.0373

Gnomad4 NFE

AF:

0.0712

Gnomad4 OTH

AF:

0.0393

Alfa

AF:

0.0621

Hom.:

737

Bravo

AF:

0.0522

TwinsUK

AF:

0.0720

AC:

267

ALSPAC

AF:

0.0677

AC:

261

ESP6500AA

AF:

0.0132

AC:

ESP6500EA

AF:

0.0707

AC:

580

ExAC

AF:

0.0562

AC:

6792

Asia WGS

AF:

0.0110

AC:

AN:

3478

EpiCase

AF:

0.0661

EpiControl

AF:

0.0620

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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	- -

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 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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.58

CADD

Benign

1.5

DANN

Benign

0.19

DEOGEN2

Benign

0.025

.;T;T;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.69

T;T;T;T

MetaRNN

Benign

0.0018

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;.;L;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.17

PROVEAN

Benign

-1.2

N;.;N;N

REVEL

Benign

0.064

Sift

Benign

0.060

T;.;T;T

Sift4G

Benign

0.19

T;T;T;T

Polyphen

0.0020

B;.;B;.

Vest4

0.13

MPC

0.049

ClinPred

0.0038

GERP RS

-3.2

Varity_R

0.039

gMVP

0.074

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