rs17101661

Positions:

chr14-64097962-G-A

Variant summary

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

The ENST00000555002.6(SYNE2):c.12122G>A(p.Arg4041His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,614,186 control chromosomes in the GnomAD database, including 211 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4041C) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.017 ( 35 hom., cov: 32)

Exomes 𝑓: 0.014 ( 176 hom. )

Consequence

SYNE2
ENST00000555002.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -2.98

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=0.0019463599).

BP6

Variant 14-64097962-G-A is Benign according to our data. Variant chr14-64097962-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 130465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64097962-G-A is described in Lovd as [Benign]. Variant chr14-64097962-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0175 (2661/152324) while in subpopulation AFR AF= 0.0281 (1167/41568). AF 95% confidence interval is 0.0267. There are 35 homozygotes in gnomad4. There are 1250 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2661 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE2	NM_182914.3 linkuse as main transcript	c.12122G>A	p.Arg4041His	missense_variant	62/116	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.12122G>A	p.Arg4041His	missense_variant	62/116	1	NM_182914.3	ENSP00000450831	P4	Q8WXH0-2

Frequencies

GnomAD3 genomes

AF:

0.0175

AC:

2660

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0281

Gnomad AMI

AF:

0.0340

Gnomad AMR

AF:

0.0151

Gnomad ASJ

AF:

0.0401

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0145

Gnomad OTH

AF:

0.0253

GnomAD3 exomes

AF:

0.0124

AC:

3113

AN:

251440

Hom.:

AF XY:

0.0121

AC XY:

1640

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.0260

Gnomad AMR exome

AF:

0.0128

Gnomad ASJ exome

AF:

0.0386

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00229

Gnomad FIN exome

AF:

0.00152

Gnomad NFE exome

AF:

0.0143

Gnomad OTH exome

AF:

0.0205

GnomAD4 exome

AF:

0.0140

AC:

20456

AN:

1461862

Hom.:

176

Cov.:

AF XY:

0.0137

AC XY:

9978

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0284

Gnomad4 AMR exome

AF:

0.0141

Gnomad4 ASJ exome

AF:

0.0370

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00235

Gnomad4 FIN exome

AF:

0.00154

Gnomad4 NFE exome

AF:

0.0149

Gnomad4 OTH exome

AF:

0.0156

GnomAD4 genome

AF:

0.0175

AC:

2661

AN:

152324

Hom.:

Cov.:

AF XY:

0.0168

AC XY:

1250

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0281

Gnomad4 AMR

AF:

0.0151

Gnomad4 ASJ

AF:

0.0401

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00269

Gnomad4 FIN

AF:

0.00160

Gnomad4 NFE

AF:

0.0145

Gnomad4 OTH

AF:

0.0251

Alfa

AF:

0.0164

Hom.:

Bravo

AF:

0.0197

TwinsUK

AF:

0.0189

AC:

ALSPAC

AF:

0.0200

AC:

ESP6500AA

AF:

0.0238

AC:

105

ESP6500EA

AF:

0.0162

AC:

139

ExAC

AF:

0.0120

AC:

1461

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0163

EpiControl

AF:

0.0164

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Emery-Dreifuss muscular dystrophy 5, autosomal dominant

Benign:3

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 13, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not specified

Benign:2

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	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.20

DANN

Benign

0.88

DEOGEN2

Benign

0.016

.;T;T;T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0089

LIST_S2

Benign

0.59

T;T;T;T;T

MetaRNN

Benign

0.0019

T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.69

N;.;N;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.69

N;.;N;N;N

REVEL

Benign

0.042

Sift

Benign

0.17

T;.;T;T;T

Sift4G

Benign

0.13

T;T;T;T;T

Polyphen

0.17

B;.;B;.;.

Vest4

0.053

MPC

0.084

ClinPred

0.00056

GERP RS

-6.1

Varity_R

0.013

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

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