chr14-64146140-C-A

Variant names:

• chr14-64146140-C-A
• rs10151658
• NM_182914.3:c.15556C>A

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.15556C>A​(p.Leu5186Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.461 in 1,605,976 control chromosomes in the GnomAD database, including 179,639 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. L5186T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.57 (27007 hom., cov: 32)
  • Exomes 𝑓: 0.45 (152632 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.568
• Publications: 43 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=6.1527055E-7).
• BP6: Variant 14-64146140-C-A is Benign according to our data. Variant chr14-64146140-C-A is described in ClinVar as Benign. ClinVar VariationId is 130480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.845 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.15556C>A	p.Leu5186Met	missense_variant	Exon 84 of 116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.15556C>A	p.Leu5186Met	missense_variant	Exon 84 of 116	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.567 AC: 86206 AN: 151934 Hom.: 26951 Cov.: 32

Gnomad AFR AF: 0.852

Gnomad AMI AF: 0.502

Gnomad AMR AF: 0.498

Gnomad ASJ AF: 0.582

Gnomad EAS AF: 0.649

Gnomad SAS AF: 0.508

Gnomad FIN AF: 0.437

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.429

Gnomad OTH AF: 0.549

GnomAD2 exomes AF: 0.497 AC: 123574 AN: 248594 AF XY: 0.489

Gnomad AFR exome AF: 0.866

Gnomad AMR exome AF: 0.482

Gnomad ASJ exome AF: 0.591

Gnomad EAS exome AF: 0.656

Gnomad FIN exome AF: 0.424

Gnomad NFE exome AF: 0.428

Gnomad OTH exome AF: 0.479

GnomAD4 exome AF: 0.450 AC: 654218 AN: 1453924 Hom.: 152632 Cov.: 31 AF XY: 0.451 AC XY: 326293 AN XY: 723444

African (AFR) AF: 0.872 AC: 29013 AN: 33276

American (AMR) AF: 0.484 AC: 21330 AN: 44060

Ashkenazi Jewish (ASJ) AF: 0.581 AC: 15132 AN: 26024

East Asian (EAS) AF: 0.611 AC: 24152 AN: 39544

South Asian (SAS) AF: 0.503 AC: 43028 AN: 85524

European-Finnish (FIN) AF: 0.423 AC: 22566 AN: 53302

Middle Eastern (MID) AF: 0.524 AC: 3009 AN: 5744

European-Non Finnish (NFE) AF: 0.422 AC: 466606 AN: 1106354

Other (OTH) AF: 0.489 AC: 29382 AN: 60096

GnomAD4 genome AF: 0.568 AC: 86315 AN: 152052 Hom.: 27007 Cov.: 32 AF XY: 0.566 AC XY: 42029 AN XY: 74310

African (AFR) AF: 0.853 AC: 35379 AN: 41496

American (AMR) AF: 0.498 AC: 7614 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 2020 AN: 3468

East Asian (EAS) AF: 0.649 AC: 3359 AN: 5172

South Asian (SAS) AF: 0.508 AC: 2450 AN: 4824

European-Finnish (FIN) AF: 0.437 AC: 4607 AN: 10548

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.429 AC: 29126 AN: 67938

Other (OTH) AF: 0.549 AC: 1159 AN: 2112

Alfa AF: 0.474 Hom.: 55596

Bravo AF: 0.586

TwinsUK AF: 0.415 AC: 1540

ALSPAC AF: 0.404 AC: 1557

ESP6500AA AF: 0.850 AC: 3745

ESP6500EA AF: 0.438 AC: 3771

ExAC AF: 0.502 AC: 60915

Asia WGS AF: 0.575 AC: 1996 AN: 3476

EpiCase AF: 0.428

EpiControl AF: 0.435

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Benign:4

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	1.9
DANN	Benign	0.52
DEOGEN2	Benign	0.0093	.;T;T;T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.084	T;T;T;T;T
MetaRNN	Benign	6.2e-7	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.32	N;.;N;.;.
PhyloP100		-0.57
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.090	N;.;N;N;N
REVEL	Benign	0.020
Sift	Benign	0.72	T;.;T;T;T
Sift4G	Benign	0.74	T;T;T;T;T
Polyphen		0.0060	B;.;B;B;.
Vest4		0.15
MPC		0.050
ClinPred		0.0024	T
GERP RS		-2.1
Varity_R		0.032
gMVP		0.16
Mutation Taster		=94/6	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: rs10151658; hg19: chr14-64612858; COSMIC: COSV59972370;