NM_182914.3:c.11944A>C

Variant names:

• chr14-64091016-A-C
• rs10137972
• NM_182914.3:c.11944A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 6.09
• Publications: 19 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 -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.11944A>C	p.Asn3982His	missense_variant	Exon 60 of 116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.11944A>C	p.Asn3982His	missense_variant	Exon 60 of 116	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.0875 AC: 13309 AN: 152148 Hom.: 761 Cov.: 33

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

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.: 31 AF XY: 0.0573 AC XY: 41639 AN XY: 727084

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

GnomAD4 genome AF: 0.0877 AC: 13357 AN: 152266 Hom.: 769 Cov.: 33 AF XY: 0.0881 AC XY: 6559 AN XY: 74466

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: 42 AN: 294

European-Non Finnish (NFE) AF: 0.0560 AC: 3809 AN: 68024

Other (OTH) AF: 0.0906 AC: 191 AN: 2108

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

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Benign:2

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 specified Benign:1

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SYNE2-related disorder Benign:1

Dec 05, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Benign	0.86
DEOGEN2	Benign	0.0034	.;T;T;T;T
Eigen	Benign	0.14
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
MetaRNN	Benign	0.0013	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;.;M;.;.
PhyloP100		6.1
PrimateAI	Benign	0.47	T
PROVEAN	Benign	1.1	N;.;N;N;N
REVEL	Benign	0.10
Sift	Benign	1.0	T;.;T;T;T
Sift4G	Uncertain	0.050	T;T;T;T;T
Polyphen		0.96	D;.;P;.;.
Vest4		0.22
MPC		0.31
ClinPred		0.043	T
GERP RS		3.4
Varity_R		0.042
gMVP		0.13
Mutation Taster		=100/0	polymorphism (auto)

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: rs10137972; hg19: chr14-64557734; COSMIC: COSV59958750; COSMIC: COSV59958750;