rs142660236

Variant names:

Variant summary

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

The NM_182914.3(SYNE2):c.15794T>C(p.Val5265Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0139 in 1,613,822 control chromosomes in the GnomAD database, including 196 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 16 hom., cov: 32)

Exomes 𝑓: 0.014 ( 180 hom. )

Consequence

SYNE2
NM_182914.3 missense, splice_region

Scores

Splicing: ADA: 0.6095

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 4.81

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=0.0029333234).

BP6

Variant 14-64158626-T-C is Benign according to our data. Variant chr14-64158626-T-C is described in ClinVar as [Benign]. Clinvar id is 130481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64158626-T-C is described in Lovd as [Benign]. Variant chr14-64158626-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0121 (1847/152276) while in subpopulation NFE AF= 0.0168 (1140/68022). AF 95% confidence interval is 0.016. There are 16 homozygotes in gnomad4. There are 940 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1847 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3 link	c.15794T>C	p.Val5265Ala	missense_variant, splice_region_variant	Exon 86 of 116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6 link	c.15794T>C	p.Val5265Ala	missense_variant, splice_region_variant	Exon 86 of 116	1	NM_182914.3	ENSP00000450831.2		Q8WXH0-2A0A0C4DGK3

Frequencies

GnomAD3 genomes

AF:

0.0122

AC:

1849

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00287

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0141

Gnomad ASJ

AF:

0.0429

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0135

Gnomad FIN

AF:

0.0106

Gnomad MID

AF:

0.0350

Gnomad NFE

AF:

0.0168

Gnomad OTH

AF:

0.0153

GnomAD3 exomes

AF:

0.0138

AC:

3454

AN:

250958

Hom.:

AF XY:

0.0149

AC XY:

2016

AN XY:

135646

show subpopulations

Gnomad AFR exome

AF:

0.00222

Gnomad AMR exome

AF:

0.0124

Gnomad ASJ exome

AF:

0.0441

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0136

Gnomad FIN exome

AF:

0.0103

Gnomad NFE exome

AF:

0.0158

Gnomad OTH exome

AF:

0.0200

GnomAD4 exome

AF:

0.0141

AC:

20596

AN:

1461546

Hom.:

180

Cov.:

AF XY:

0.0144

AC XY:

10492

AN XY:

727082

show subpopulations

Gnomad4 AFR exome

AF:

0.00287

Gnomad4 AMR exome

AF:

0.0130

Gnomad4 ASJ exome

AF:

0.0436

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0141

Gnomad4 FIN exome

AF:

0.00952

Gnomad4 NFE exome

AF:

0.0143

Gnomad4 OTH exome

AF:

0.0157

GnomAD4 genome

AF:

0.0121

AC:

1847

AN:

152276

Hom.:

Cov.:

AF XY:

0.0126

AC XY:

940

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00286

Gnomad4 AMR

AF:

0.0141

Gnomad4 ASJ

AF:

0.0429

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0139

Gnomad4 FIN

AF:

0.0106

Gnomad4 NFE

AF:

0.0168

Gnomad4 OTH

AF:

0.0151

Alfa

AF:

0.0164

Hom.:

Bravo

AF:

0.0117

TwinsUK

AF:

0.0127

AC:

ALSPAC

AF:

0.0125

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.0170

AC:

146

ExAC

AF:

0.0134

AC:

1624

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.0174

EpiControl

AF:

0.0197

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant

Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.069

.;T;T;T;T

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

T;T;T;T;T

MetaRNN

Benign

0.0029

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

M;.;M;.;.

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.1

D;.;D;D;D

REVEL

Benign

0.085

Sift

Benign

0.031

D;.;D;D;D

Sift4G

Uncertain

0.052

T;T;T;T;T

Polyphen

0.41

B;.;B;P;.

Vest4

0.52

MPC

0.18

ClinPred

0.013

GERP RS

5.8

Varity_R

0.13

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.61

dbscSNV1_RF

Benign

0.57

SpliceAI score (max)

0.020

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