chr14-64091016-A-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_182914.3(SYNE2):c.11944A>C(p.Asn3982His) variant causes a missense change. The variant allele was found at a frequency of 0.0609 in 1,613,786 control chromosomes in the GnomAD database, including 3,633 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N3982D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.088 ( 769 hom., cov: 33)

Exomes 𝑓: 0.058 ( 2864 hom. )

Consequence

SYNE2
NM_182914.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.09

Publications

19 publications found

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 Gene-Disease associations (from GenCC):

male infertility with azoospermia or oligozoospermia due to single gene mutation
Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center
familial medullary thyroid carcinoma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ovarian dysgenesis 8
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ESR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0012866855).

BP6

Variant 14-64091016-A-C is Benign according to our data. Variant chr14-64091016-A-C is described in ClinVar as Benign. ClinVar VariationId is 130461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182914.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	NM_182914.3	MANE Select	c.11944A>C	p.Asn3982His	missense	Exon 60 of 116	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.11944A>C	p.Asn3982His	missense	Exon 60 of 115	NP_055995.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYNE2	ENST00000555002.6	TSL:1 MANE Select	c.11944A>C	p.Asn3982His	missense	Exon 60 of 116	ENSP00000450831.2	Q8WXH0-2
SYNE2	ENST00000344113.8	TSL:1	c.11944A>C	p.Asn3982His	missense	Exon 60 of 115	ENSP00000341781.4	Q8WXH0-1
SYNE2	ENST00000394768.6	TSL:1	n.1477A>C		non_coding_transcript_exon	Exon 8 of 63

Frequencies

GnomAD3 genomes

AF:

0.0875

AC:

13309

AN:

152148

Hom.:

761

Cov.:

show subpopulations

Gnomad AFR

AF:

0.159

Gnomad AMI

AF:

0.150

Gnomad AMR

AF:

0.0586

Gnomad ASJ

AF:

0.0769

Gnomad EAS

AF:

0.0721

Gnomad SAS

AF:

0.0410

Gnomad FIN

AF:

0.0760

Gnomad MID

AF:

0.142

Gnomad NFE

AF:

0.0560

Gnomad OTH

AF:

0.0911

GnomAD2 exomes

AF:

0.0639

AC:

16030

AN:

250994

AF XY:

0.0621

show subpopulations

Gnomad AFR exome

AF:

0.156

Gnomad AMR exome

AF:

0.0412

Gnomad ASJ exome

AF:

0.0764

Gnomad EAS exome

AF:

0.0818

Gnomad FIN exome

AF:

0.0744

Gnomad NFE exome

AF:

0.0588

Gnomad OTH exome

AF:

0.0718

GnomAD4 exome

AF:

0.0581

AC:

84913

AN:

1461520

Hom.:

2864

Cov.:

AF XY:

0.0573

AC XY:

41639

AN XY:

727084

show subpopulations

African (AFR)

AF:

0.168

AC:

5624

AN:

33462

American (AMR)

AF:

0.0451

AC:

2019

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0722

AC:

1887

AN:

26132

East Asian (EAS)

AF:

0.0587

AC:

2327

AN:

39668

South Asian (SAS)

AF:

0.0341

AC:

2938

AN:

86254

European-Finnish (FIN)

AF:

0.0703

AC:

3753

AN:

53414

Middle Eastern (MID)

AF:

0.0884

AC:

510

AN:

5766

European-Non Finnish (NFE)

AF:

0.0557

AC:

61880

AN:

1111720

Other (OTH)

AF:

0.0658

AC:

3975

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

3911

7822

11734

15645

19556

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2358

4716

7074

9432

11790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0877

AC:

13357

AN:

152266

Hom.:

769

Cov.:

AF XY:

0.0881

AC XY:

6559

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.160

AC:

6638

AN:

41538

American (AMR)

AF:

0.0585

AC:

895

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0769

AC:

267

AN:

3472

East Asian (EAS)

AF:

0.0723

AC:

375

AN:

5188

South Asian (SAS)

AF:

0.0408

AC:

197

AN:

4826

European-Finnish (FIN)

AF:

0.0760

AC:

806

AN:

10608

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0560

AC:

3809

AN:

68024

Other (OTH)

AF:

0.0906

AC:

191

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

620

1240

1859

2479

3099

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

138

276

414

552

690

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0662

Hom.:

1257

Bravo

AF:

0.0912

TwinsUK

AF:

0.0520

AC:

193

ALSPAC

AF:

0.0581

AC:

224

ESP6500AA

AF:

0.146

AC:

645

ESP6500EA

AF:

0.0555

AC:

477

ExAC

AF:

0.0655

AC:

7948

Asia WGS

AF:

0.0790

AC:

273

AN:

3478

EpiCase

AF:

0.0633

EpiControl

AF:

0.0636

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Emery-Dreifuss muscular dystrophy 5, autosomal dominant (2)

not provided (2)

not specified (1)

SYNE2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.0034

Eigen

Benign

0.14

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.0013

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

PhyloP100

6.1

PrimateAI

Benign

0.47

PROVEAN

Benign

1.1

REVEL

Benign

0.10

Sift

Benign

1.0

Sift4G

Uncertain

0.050

Polyphen

0.96

Vest4

0.22

MPC

0.31

ClinPred

0.043

GERP RS

3.4

Varity_R

0.042

gMVP

0.13

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over