rs9944035

Positions:

chr14-63981058-T-C

Variant summary

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

The NM_182914.3(SYNE2):c.1721T>C(p.Ile574Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0776 in 1,593,248 control chromosomes in the GnomAD database, including 5,821 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.092 ( 699 hom., cov: 32)

Exomes 𝑓: 0.076 ( 5122 hom. )

Consequence

SYNE2
NM_182914.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.30

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=0.0016518831).

BP6

Variant 14-63981058-T-C is Benign according to our data. Variant chr14-63981058-T-C is described in ClinVar as [Benign]. Clinvar id is 130486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-63981058-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.163 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.1721T>C	p.Ile574Thr	missense_variant	16/116	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.1721T>C	p.Ile574Thr	missense_variant	16/116	1	NM_182914.3	ENSP00000450831.2		Q8WXH0-2A0A0C4DGK3

Frequencies

GnomAD3 genomes

AF:

0.0920

AC:

13987

AN:

152034

Hom.:

700

Cov.:

show subpopulations

Gnomad AFR

AF:

0.113

Gnomad AMI

AF:

0.00879

Gnomad AMR

AF:

0.113

Gnomad ASJ

AF:

0.135

Gnomad EAS

AF:

0.108

Gnomad SAS

AF:

0.173

Gnomad FIN

AF:

0.0790

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.0680

Gnomad OTH

AF:

0.105

GnomAD3 exomes

AF:

0.101

AC:

25062

AN:

249116

Hom.:

1496

AF XY:

0.103

AC XY:

13861

AN XY:

135156

show subpopulations

Gnomad AFR exome

AF:

0.109

Gnomad AMR exome

AF:

0.125

Gnomad ASJ exome

AF:

0.147

Gnomad EAS exome

AF:

0.119

Gnomad SAS exome

AF:

0.163

Gnomad FIN exome

AF:

0.0815

Gnomad NFE exome

AF:

0.0712

Gnomad OTH exome

AF:

0.105

GnomAD4 exome

AF:

0.0761

AC:

109645

AN:

1441096

Hom.:

5122

Cov.:

AF XY:

0.0788

AC XY:

56618

AN XY:

718200

show subpopulations

Gnomad4 AFR exome

AF:

0.113

Gnomad4 AMR exome

AF:

0.125

Gnomad4 ASJ exome

AF:

0.149

Gnomad4 EAS exome

AF:

0.110

Gnomad4 SAS exome

AF:

0.159

Gnomad4 FIN exome

AF:

0.0826

Gnomad4 NFE exome

AF:

0.0622

Gnomad4 OTH exome

AF:

0.0889

GnomAD4 genome

AF:

0.0919

AC:

13985

AN:

152152

Hom.:

699

Cov.:

AF XY:

0.0951

AC XY:

7071

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.112

Gnomad4 AMR

AF:

0.113

Gnomad4 ASJ

AF:

0.135

Gnomad4 EAS

AF:

0.108

Gnomad4 SAS

AF:

0.173

Gnomad4 FIN

AF:

0.0790

Gnomad4 NFE

AF:

0.0680

Gnomad4 OTH

AF:

0.102

Alfa

AF:

0.0808

Hom.:

1349

Bravo

AF:

0.0941

TwinsUK

AF:

0.0628

AC:

233

ALSPAC

AF:

0.0571

AC:

220

ESP6500AA

AF:

0.106

AC:

381

ESP6500EA

AF:

0.0705

AC:

574

ExAC

AF:

0.0992

AC:

11986

Asia WGS

AF:

0.131

AC:

454

AN:

3476

EpiCase

AF:

0.0823

EpiControl

AF:

0.0841

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 29, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Emery-Dreifuss muscular dystrophy 5, autosomal dominant

Benign:3

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	Jan 31, 2024	- -

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

0.33

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.47

DEOGEN2

Benign

0.063

.;T;T;T

Eigen

Benign

0.13

Eigen_PC

Benign

0.048

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.73

T;T;T;T

MetaRNN

Benign

0.0017

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;.;L;.

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-2.5

D;.;D;D

REVEL

Benign

0.15

Sift

Benign

0.040

D;.;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

0.95

P;.;P;.

Vest4

0.34

MPC

0.069

ClinPred

0.038

GERP RS

5.6

Varity_R

0.11

gMVP

0.18

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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