rs34449017

Positions:

chr14-63991029-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000555002.6(SYNE2):c.2560C>G(p.Gln854Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00372 in 1,614,082 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 14 hom. )

Consequence

SYNE2
ENST00000555002.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.35

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=0.0079833865).

BP6

Variant 14-63991029-C-G is Benign according to our data. Variant chr14-63991029-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 281307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00245 (373/152250) while in subpopulation NFE AF= 0.00412 (280/68020). AF 95% confidence interval is 0.00372. There are 0 homozygotes in gnomad4. There are 178 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 373 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE2	NM_182914.3 linkuse as main transcript	c.2560C>G	p.Gln854Glu	missense_variant	21/116	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.2560C>G	p.Gln854Glu	missense_variant	21/116	1	NM_182914.3	ENSP00000450831	P4	Q8WXH0-2

Frequencies

GnomAD3 genomes

AF:

0.00245

AC:

373

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00412

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00228

AC:

570

AN:

249476

Hom.:

AF XY:

0.00227

AC XY:

307

AN XY:

135340

show subpopulations

Gnomad AFR exome

AF:

0.00116

Gnomad AMR exome

AF:

0.00249

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000654

Gnomad FIN exome

AF:

0.00121

Gnomad NFE exome

AF:

0.00361

Gnomad OTH exome

AF:

0.00182

GnomAD4 exome

AF:

0.00385

AC:

5633

AN:

1461832

Hom.:

Cov.:

AF XY:

0.00367

AC XY:

2672

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.000806

Gnomad4 AMR exome

AF:

0.00250

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000939

Gnomad4 FIN exome

AF:

0.000899

Gnomad4 NFE exome

AF:

0.00456

Gnomad4 OTH exome

AF:

0.00482

GnomAD4 genome

AF:

0.00245

AC:

373

AN:

152250

Hom.:

Cov.:

AF XY:

0.00239

AC XY:

178

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.000746

Gnomad4 AMR

AF:

0.00294

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000623

Gnomad4 FIN

AF:

0.000944

Gnomad4 NFE

AF:

0.00412

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00343

Hom.:

Bravo

AF:

0.00242

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.00217

AC:

ESP6500EA

AF:

0.00488

AC:

ExAC

AF:

0.00217

AC:

262

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely 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	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	SYNE2: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Emery-Dreifuss muscular dystrophy 5, autosomal dominant

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 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. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 11, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.020

.;T;T;T

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.84

T;T;T;T

M_CAP

Benign

0.0048

MetaRNN

Benign

0.0080

T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.1

M;.;M;.

MutationTaster

Benign

1.0

D;N;N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.6

N;N;N;N

REVEL

Benign

0.12

Sift

Uncertain

0.0090

D;T;D;D

Sift4G

Uncertain

0.013

D;D;D;D

Polyphen

0.87

P;.;P;.

Vest4

0.19

MVP

0.59

MPC

0.10

ClinPred

0.018

GERP RS

6.1

Varity_R

0.14

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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