rs143646847

Variant names:

• chr14-64126342-G-A
• rs143646847
• NM_182914.3:c.13570G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_182914.3(SYNE2):​c.13570G>A​(p.Glu4524Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0005 in 1,613,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (0 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 4.56
• Publications: 1 publications found

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]

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)

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14381).
• BP6: Variant 14-64126342-G-A is Benign according to our data. Variant chr14-64126342-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 313589.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000276 (42/152146) while in subpopulation NFE AF = 0.000529 (36/68018). AF 95% confidence interval is 0.000392. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 42 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.13570G>A	p.Glu4524Lys	missense_variant	Exon 72 of 116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.13570G>A	p.Glu4524Lys	missense_variant	Exon 72 of 116	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000163 AC: 41 AN: 251090 AF XY: 0.000125

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000317

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000523 AC: 765 AN: 1461626 Hom.: 0 Cov.: 32 AF XY: 0.000525 AC XY: 382 AN XY: 727128

African (AFR) AF: 0.000149 AC: 5 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000631 AC: 702 AN: 1111766

Other (OTH) AF: 0.000894 AC: 54 AN: 60392

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.000256 AC XY: 19 AN XY: 74326

African (AFR) AF: 0.000145 AC: 6 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000360 Hom.: 0

Bravo AF: 0.000321

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000818

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Uncertain:1 Benign:1

May 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 4524 of the SYNE2 protein (p.Glu4524Lys). This variant is present in population databases (rs143646847, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SYNE2-related conditions. ClinVar contains an entry for this variant (Variation ID: 313589). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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. -

not specified Uncertain:1

May 29, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.13570G>A (p.E4524K) alteration is located in exon 72 (coding exon 71) of the SYNE2 gene. This alteration results from a G to A substitution at nucleotide position 13570, causing the glutamic acid (E) at amino acid position 4524 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SYNE2: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Benign	0.91
DEOGEN2	Benign	0.014	.;T;T;T;T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.1	M;.;M;.;.
PhyloP100		4.6
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.1	N;.;N;N;N
REVEL	Benign	0.066
Sift	Benign	0.18	T;.;T;T;T
Sift4G	Uncertain	0.013	D;D;D;D;D
Polyphen		0.87	P;.;P;.;.
Vest4		0.45
MVP		0.58
MPC		0.20
ClinPred		0.077	T
GERP RS		5.8
Varity_R		0.091
gMVP		0.21
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs143646847; hg19: chr14-64593060;