rs192061494

Positions:

chr14-63982666-C-T

Variant summary

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

The NM_182914.3(SYNE2):c.1873C>T(p.His625Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,613,832 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H625H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00097 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 2 hom. )

Consequence

SYNE2
NM_182914.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.60

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=0.005859375).

BP6

Variant 14-63982666-C-T is Benign according to our data. Variant chr14-63982666-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 282409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000974 (148/152028) while in subpopulation AMR AF= 0.00308 (47/15262). AF 95% confidence interval is 0.00238. There are 0 homozygotes in gnomad4. There are 76 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 148 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3 linkuse as main transcript	c.1873C>T	p.His625Tyr	missense_variant	17/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6 linkuse as main transcript	c.1873C>T	p.His625Tyr	missense_variant	17/116	1	NM_182914.3	P4	Q8WXH0-2

Frequencies

GnomAD3 genomes

AF:

0.000981

AC:

149

AN:

151912

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000285

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00109

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.000946

AC:

236

AN:

249548

Hom.:

AF XY:

0.000879

AC XY:

119

AN XY:

135390

show subpopulations

Gnomad AFR exome

AF:

0.000517

Gnomad AMR exome

AF:

0.00125

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000603

Gnomad NFE exome

AF:

0.00130

Gnomad OTH exome

AF:

0.00281

GnomAD4 exome

AF:

0.00138

AC:

2013

AN:

1461804

Hom.:

Cov.:

AF XY:

0.00127

AC XY:

926

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.000329

Gnomad4 AMR exome

AF:

0.00114

Gnomad4 ASJ exome

AF:

0.000651

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000580

Gnomad4 NFE exome

AF:

0.00160

Gnomad4 OTH exome

AF:

0.00189

GnomAD4 genome

AF:

0.000974

AC:

148

AN:

152028

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.000458

Gnomad4 AMR

AF:

0.00308

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000285

Gnomad4 NFE

AF:

0.00109

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00103

Hom.:

Bravo

AF:

0.00134

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000259

AC:

ESP6500EA

AF:

0.00217

AC:

ExAC

AF:

0.000869

AC:

105

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00131

EpiControl

AF:

0.00113

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

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	SYNE2: BS1 -
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 17, 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)

Aug 11, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.068

.;T;T;T

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.76

T;T;T;T

MetaRNN

Benign

0.0059

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.3

M;.;M;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-4.0

D;.;D;D

REVEL

Benign

0.23

Sift

Benign

0.039

D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.13

B;.;B;.

Vest4

0.34

MVP

0.35

MPC

0.055

ClinPred

0.024

GERP RS

4.1

Varity_R

0.18

gMVP

0.51

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