chr14-64210033-C-T

Position:

chr14-64210033-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.18632C>T(p.Thr6211Met) variant causes a missense change. The variant allele was found at a frequency of 0.00695 in 1,614,120 control chromosomes in the GnomAD database, including 60 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 (★★).

Frequency

Genomes: 𝑓 0.0040 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0072 ( 57 hom. )

Consequence

SYNE2
NM_182914.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:11

Conservation

PhyloP100: 4.72

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:

ESR2 (HGNC:3468): (estrogen receptor 2) This gene encodes a member of the family of estrogen receptors and superfamily of nuclear receptor transcription factors. The gene product contains an N-terminal DNA binding domain and C-terminal ligand binding domain and is localized to the nucleus, cytoplasm, and mitochondria. Upon binding to 17beta-estradiol or related ligands, the encoded protein forms homo- or hetero-dimers that interact with specific DNA sequences to activate transcription. Some isoforms dominantly inhibit the activity of other estrogen receptor family members. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been fully characterized. [provided by RefSeq, Jul 2008]

ESR2 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=0.00664407).

BP6

Variant 14-64210033-C-T is Benign according to our data. Variant chr14-64210033-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64210033-C-T is described in Lovd as [Pathogenic]. Variant chr14-64210033-C-T is described in Lovd as [Likely_benign]. Variant chr14-64210033-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00403 (614/152312) while in subpopulation NFE AF= 0.0066 (449/68026). AF 95% confidence interval is 0.0061. There are 3 homozygotes in gnomad4. There are 268 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 614 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE2	NM_182914.3 linkuse as main transcript	c.18632C>T	p.Thr6211Met	missense_variant	103/116	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.18632C>T	p.Thr6211Met	missense_variant	103/116	1	NM_182914.3	ENSP00000450831	P4	Q8WXH0-2

Frequencies

GnomAD3 genomes

AF:

0.00403

AC:

613

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00594

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00658

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00476

AC:

1195

AN:

250900

Hom.:

AF XY:

0.00474

AC XY:

643

AN XY:

135782

show subpopulations

Gnomad AFR exome

AF:

0.000989

Gnomad AMR exome

AF:

0.00197

Gnomad ASJ exome

AF:

0.00328

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00124

Gnomad FIN exome

AF:

0.00658

Gnomad NFE exome

AF:

0.00766

Gnomad OTH exome

AF:

0.00457

GnomAD4 exome

AF:

0.00725

AC:

10598

AN:

1461808

Hom.:

Cov.:

AF XY:

0.00702

AC XY:

5104

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.000986

Gnomad4 AMR exome

AF:

0.00172

Gnomad4 ASJ exome

AF:

0.00402

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00111

Gnomad4 FIN exome

AF:

0.00666

Gnomad4 NFE exome

AF:

0.00864

Gnomad4 OTH exome

AF:

0.00515

GnomAD4 genome

AF:

0.00403

AC:

614

AN:

152312

Hom.:

Cov.:

AF XY:

0.00360

AC XY:

268

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00130

Gnomad4 AMR

AF:

0.00150

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.00594

Gnomad4 NFE

AF:

0.00660

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00493

Hom.:

Bravo

AF:

0.00385

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00628

AC:

ExAC

AF:

0.00503

AC:

611

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00611

EpiControl

AF:

0.00747

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant

Pathogenic:1Benign:4

Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2007	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 03, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 17, 2016	- -

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 29, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	SYNE2: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

SYNE2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 01, 2019

This variant is classified as 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

0.10

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

CADD

Uncertain

DANN

Benign

0.94

DEOGEN2

Benign

0.035

.;T;T;T;T

Eigen

Benign

0.13

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.95

D;D;D;D;D

MetaRNN

Benign

0.0066

T;T;T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Benign

0.0

N;.;N;.;.

MutationTaster

Benign

1.0

A;A;A;A;A;A;A;A;A

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-3.3

D;.;D;D;D

REVEL

Benign

0.15

Sift

Uncertain

0.0010

D;.;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D;D

Polyphen

1.0

D;.;P;P;.

Vest4

0.37

MVP

0.48

MPC

0.28

ClinPred

0.063

GERP RS

4.7

Varity_R

0.30

gMVP

0.16

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