NM_182914.3:c.17202C>A

Variant names:

• chr14-64170429-C-A
• rs7161192
• NM_182914.3:c.17202C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_182914.3(SYNE2):​c.17202C>A​(p.Leu5734Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 1,612,700 control chromosomes in the GnomAD database, including 85,557 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (8715 hom., cov: 32)
  • Exomes 𝑓: 0.32 (76842 hom.)
• Consequence: SYNE2 NM_182914.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.220
• Publications: 26 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 14-64170429-C-A is Benign according to our data. Variant chr14-64170429-C-A is described in ClinVar as Benign. ClinVar VariationId is 130485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.22 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.17202C>A	p.Leu5734Leu	synonymous_variant	Exon 94 of 116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.17202C>A	p.Leu5734Leu	synonymous_variant	Exon 94 of 116	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.335 AC: 50949 AN: 151914 Hom.: 8715 Cov.: 32

Gnomad AFR AF: 0.351

Gnomad AMI AF: 0.290

Gnomad AMR AF: 0.291

Gnomad ASJ AF: 0.376

Gnomad EAS AF: 0.566

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.338

Gnomad MID AF: 0.313

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.318

GnomAD2 exomes AF: 0.329 AC: 81919 AN: 249010 AF XY: 0.327

Gnomad AFR exome AF: 0.358

Gnomad AMR exome AF: 0.260

Gnomad ASJ exome AF: 0.376

Gnomad EAS exome AF: 0.572

Gnomad FIN exome AF: 0.328

Gnomad NFE exome AF: 0.315

Gnomad OTH exome AF: 0.314

GnomAD4 exome AF: 0.321 AC: 469584 AN: 1460668 Hom.: 76842 Cov.: 47 AF XY: 0.321 AC XY: 233105 AN XY: 726548

African (AFR) AF: 0.353 AC: 11818 AN: 33470

American (AMR) AF: 0.266 AC: 11832 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 9567 AN: 26094

East Asian (EAS) AF: 0.540 AC: 21411 AN: 39676

South Asian (SAS) AF: 0.287 AC: 24691 AN: 86086

European-Finnish (FIN) AF: 0.332 AC: 17693 AN: 53326

Middle Eastern (MID) AF: 0.302 AC: 1740 AN: 5766

European-Non Finnish (NFE) AF: 0.316 AC: 350900 AN: 1111380

Other (OTH) AF: 0.330 AC: 19932 AN: 60356

GnomAD4 genome AF: 0.335 AC: 50975 AN: 152032 Hom.: 8715 Cov.: 32 AF XY: 0.336 AC XY: 24952 AN XY: 74312

African (AFR) AF: 0.351 AC: 14568 AN: 41468

American (AMR) AF: 0.291 AC: 4446 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.376 AC: 1303 AN: 3468

East Asian (EAS) AF: 0.567 AC: 2925 AN: 5162

South Asian (SAS) AF: 0.288 AC: 1387 AN: 4816

European-Finnish (FIN) AF: 0.338 AC: 3564 AN: 10560

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.320 AC: 21767 AN: 67958

Other (OTH) AF: 0.314 AC: 663 AN: 2114

Alfa AF: 0.328 Hom.: 39729

Bravo AF: 0.336

Asia WGS AF: 0.371 AC: 1287 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

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

-

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

- -

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	6.3
DANN	Benign	0.76
PhyloP100		0.22
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: rs7161192; hg19: chr14-64637147; COSMIC: COSV107422212; COSMIC: COSV107422212;