rs2792205

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.12001T>C(p.Trp4001Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0727 in 1,612,466 control chromosomes in the GnomAD database, including 5,112 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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. W4001Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.089 ( 676 hom., cov: 32)

Exomes 𝑓: 0.071 ( 4436 hom. )

Consequence

SYNE2
NM_182914.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 4.57

Publications

15 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=0.0012952387).

BP6

Variant 14-64093373-T-C is Benign according to our data. Variant chr14-64093373-T-C is described in ClinVar as Benign. ClinVar VariationId is 130462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.133 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.12001T>C	p.Trp4001Arg	missense	Exon 61 of 116	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.12001T>C	p.Trp4001Arg	missense	Exon 61 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.12001T>C	p.Trp4001Arg	missense	Exon 61 of 116	ENSP00000450831.2	Q8WXH0-2
SYNE2	ENST00000344113.8	TSL:1	c.12001T>C	p.Trp4001Arg	missense	Exon 61 of 115	ENSP00000341781.4	Q8WXH0-1
SYNE2	ENST00000394768.6	TSL:1	n.1534T>C		non_coding_transcript_exon	Exon 9 of 63

Frequencies

GnomAD3 genomes

AF:

0.0893

AC:

13582

AN:

152116

Hom.:

676

Cov.:

show subpopulations

Gnomad AFR

AF:

0.130

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0799

Gnomad ASJ

AF:

0.172

Gnomad EAS

AF:

0.110

Gnomad SAS

AF:

0.143

Gnomad FIN

AF:

0.0569

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.0628

Gnomad OTH

AF:

0.0963

GnomAD2 exomes

AF:

0.0859

AC:

21585

AN:

251362

AF XY:

0.0879

show subpopulations

Gnomad AFR exome

AF:

0.132

Gnomad AMR exome

AF:

0.0486

Gnomad ASJ exome

AF:

0.181

Gnomad EAS exome

AF:

0.118

Gnomad FIN exome

AF:

0.0583

Gnomad NFE exome

AF:

0.0664

Gnomad OTH exome

AF:

0.0992

GnomAD4 exome

AF:

0.0710

AC:

103713

AN:

1460232

Hom.:

4436

Cov.:

AF XY:

0.0735

AC XY:

53379

AN XY:

726496

show subpopulations

African (AFR)

AF:

0.135

AC:

4502

AN:

33398

American (AMR)

AF:

0.0523

AC:

2339

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.185

AC:

4822

AN:

26106

East Asian (EAS)

AF:

0.115

AC:

4560

AN:

39678

South Asian (SAS)

AF:

0.137

AC:

11839

AN:

86178

European-Finnish (FIN)

AF:

0.0588

AC:

3141

AN:

53410

Middle Eastern (MID)

AF:

0.104

AC:

602

AN:

5762

European-Non Finnish (NFE)

AF:

0.0600

AC:

66683

AN:

1110658

Other (OTH)

AF:

0.0866

AC:

5225

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

4911

9822

14732

19643

24554

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2640

5280

7920

10560

13200

<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:

0.0893

AC:

13587

AN:

152234

Hom.:

676

Cov.:

AF XY:

0.0908

AC XY:

6760

AN XY:

74446

show subpopulations

African (AFR)

AF:

0.130

AC:

5401

AN:

41544

American (AMR)

AF:

0.0797

AC:

1219

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.172

AC:

597

AN:

3466

East Asian (EAS)

AF:

0.110

AC:

570

AN:

5180

South Asian (SAS)

AF:

0.142

AC:

684

AN:

4818

European-Finnish (FIN)

AF:

0.0569

AC:

604

AN:

10614

Middle Eastern (MID)

AF:

0.122

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0628

AC:

4270

AN:

68010

Other (OTH)

AF:

0.0953

AC:

201

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

639

1278

1918

2557

3196

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

164

328

492

656

820

<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:

0.0898

Hom.:

569

Bravo

AF:

0.0910

TwinsUK

AF:

0.0572

AC:

212

ALSPAC

AF:

0.0633

AC:

244

ESP6500AA

AF:

0.115

AC:

508

ESP6500EA

AF:

0.0584

AC:

502

ExAC

AF:

0.0873

AC:

10605

Asia WGS

AF:

0.114

AC:

398

AN:

3478

EpiCase

AF:

0.0698

EpiControl

AF:

0.0751

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Emery-Dreifuss muscular dystrophy 5, autosomal dominant (3)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.061

Eigen

Benign

-0.19

Eigen_PC

Benign

0.053

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0013

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

4.6

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.052

Sift

Benign

0.20

Sift4G

Benign

0.16

Polyphen

0.0010

Vest4

0.19

MutPred

0.36

Gain of disorder (P = 0.003)

MPC

0.074

ClinPred

0.032

GERP RS

5.9

Varity_R

0.47

gMVP

0.41

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