Genetic Variant SYNE2:p.Leu6619Leu (chr14-64219407-G-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_182914.3(SYNE2):c.19857G>T(p.Leu6619Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 1,613,108 control chromosomes in the GnomAD database, including 58,800 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 4771 hom., cov: 31)

Exomes 𝑓: 0.27 ( 54029 hom. )

Consequence

SYNE2
NM_182914.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.932

Publications

18 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 14-64219407-G-T is Benign according to our data. Variant chr14-64219407-G-T is described in ClinVar as Benign. ClinVar VariationId is 130490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.932 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.277 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SYNE2	NM_182914.3	MANE Select	c.19857G>T	p.Leu6619Leu	synonymous	Exon 110 of 116	NP_878918.2
SYNE2	NM_015180.6		c.19788G>T	p.Leu6596Leu	synonymous	Exon 109 of 115	NP_055995.4
SYNE2	NM_182913.4		c.759G>T	p.Leu253Leu	synonymous	Exon 5 of 11	NP_878917.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SYNE2	ENST00000555002.6	TSL:1 MANE Select	c.19857G>T	p.Leu6619Leu	synonymous	Exon 110 of 116	ENSP00000450831.2
SYNE2	ENST00000344113.8	TSL:1	c.19788G>T	p.Leu6596Leu	synonymous	Exon 109 of 115	ENSP00000341781.4
SYNE2	ENST00000458046.6	TSL:1	c.759G>T	p.Leu253Leu	synonymous	Exon 5 of 11	ENSP00000391937.2

Frequencies

GnomAD3 genomes

AF:

0.245

AC:

37223

AN:

151888

Hom.:

4775

Cov.:

show subpopulations

Gnomad AFR

AF:

0.211

Gnomad AMI

AF:

0.412

Gnomad AMR

AF:

0.205

Gnomad ASJ

AF:

0.331

Gnomad EAS

AF:

0.111

Gnomad SAS

AF:

0.254

Gnomad FIN

AF:

0.221

Gnomad MID

AF:

0.335

Gnomad NFE

AF:

0.280

Gnomad OTH

AF:

0.262

GnomAD2 exomes

AF:

0.236

AC:

59290

AN:

250938

AF XY:

0.243

show subpopulations

Gnomad AFR exome

AF:

0.208

Gnomad AMR exome

AF:

0.136

Gnomad ASJ exome

AF:

0.332

Gnomad EAS exome

AF:

0.0964

Gnomad FIN exome

AF:

0.230

Gnomad NFE exome

AF:

0.281

Gnomad OTH exome

AF:

0.251

GnomAD4 exome

AF:

0.267

AC:

390347

AN:

1461102

Hom.:

54029

Cov.:

AF XY:

0.267

AC XY:

194226

AN XY:

726894

show subpopulations

African (AFR)

AF:

0.207

AC:

6921

AN:

33476

American (AMR)

AF:

0.144

AC:

6445

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.331

AC:

8652

AN:

26132

East Asian (EAS)

AF:

0.111

AC:

4406

AN:

39698

South Asian (SAS)

AF:

0.255

AC:

22015

AN:

86226

European-Finnish (FIN)

AF:

0.229

AC:

12234

AN:

53340

Middle Eastern (MID)

AF:

0.280

AC:

1615

AN:

5768

European-Non Finnish (NFE)

AF:

0.281

AC:

312101

AN:

1111378

Other (OTH)

AF:

0.264

AC:

15958

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

14020

28040

42061

56081

70101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10254

20508

30762

41016

51270

<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:

0.245

AC:

37228

AN:

152006

Hom.:

4771

Cov.:

AF XY:

0.240

AC XY:

17838

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.211

AC:

8761

AN:

41444

American (AMR)

AF:

0.205

AC:

3128

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.331

AC:

1148

AN:

3472

East Asian (EAS)

AF:

0.110

AC:

571

AN:

5178

South Asian (SAS)

AF:

0.254

AC:

1219

AN:

4802

European-Finnish (FIN)

AF:

0.221

AC:

2335

AN:

10566

Middle Eastern (MID)

AF:

0.330

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.280

AC:

19048

AN:

67950

Other (OTH)

AF:

0.259

AC:

547

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

1394

2788

4181

5575

6969

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

392

784

1176

1568

1960

<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:

0.263

Hom.:

4347

Bravo

AF:

0.240

Asia WGS

AF:

0.199

AC:

695

AN:

3478

EpiCase

AF:

0.288

EpiControl

AF:

0.291

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

Jul 15, 2021

Genome-Nilou Lab

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

Jan 13, 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.

not provided

Benign:2

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

not specified

Benign:1

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.60

(source)

DANN

Benign

0.57

PhyloP100

0.93

Mutation Taster

=97/3

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over