NM_182914.3:c.13707+10T>C

Variant names:

• chr14-64126489-T-C
• rs61987277
• NM_182914.3:c.13707+10T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_182914.3(SYNE2):​c.13707+10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0171 in 1,614,110 control chromosomes in the GnomAD database, including 276 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (46 hom., cov: 32)
  • Exomes 𝑓: 0.017 (230 hom.)
• Consequence: SYNE2 NM_182914.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.947
• Publications: 4 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 (BayesDel_noAF=-0.87).
• BP6: Variant 14-64126489-T-C is Benign according to our data. Variant chr14-64126489-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 313591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0225 (3433/152290) while in subpopulation AFR AF = 0.0372 (1546/41542). AF 95% confidence interval is 0.0357. There are 46 homozygotes in GnomAd4. There are 1699 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3433 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.13707+10T>C		intron_variant	Intron 72 of 115	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.13707+10T>C		intron_variant	Intron 72 of 115	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.0225 AC: 3427 AN: 152172 Hom.: 46 Cov.: 32

Gnomad AFR AF: 0.0372

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0189

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0227

Gnomad FIN AF: 0.0284

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0153

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0168 AC: 4213 AN: 251078 AF XY: 0.0171

Gnomad AFR exome AF: 0.0385

Gnomad AMR exome AF: 0.00738

Gnomad ASJ exome AF: 0.0180

Gnomad EAS exome AF: 0.000436

Gnomad FIN exome AF: 0.0255

Gnomad NFE exome AF: 0.0157

Gnomad OTH exome AF: 0.0196

GnomAD4 exome AF: 0.0166 AC: 24222 AN: 1461820 Hom.: 230 Cov.: 32 AF XY: 0.0167 AC XY: 12115 AN XY: 727196

African (AFR) AF: 0.0380 AC: 1273 AN: 33480

American (AMR) AF: 0.00778 AC: 348 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0184 AC: 482 AN: 26136

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39698

South Asian (SAS) AF: 0.0219 AC: 1892 AN: 86258

European-Finnish (FIN) AF: 0.0258 AC: 1378 AN: 53414

Middle Eastern (MID) AF: 0.0250 AC: 144 AN: 5768

European-Non Finnish (NFE) AF: 0.0158 AC: 17532 AN: 1111958

Other (OTH) AF: 0.0192 AC: 1161 AN: 60390

GnomAD4 genome AF: 0.0225 AC: 3433 AN: 152290 Hom.: 46 Cov.: 32 AF XY: 0.0228 AC XY: 1699 AN XY: 74458

African (AFR) AF: 0.0372 AC: 1546 AN: 41542

American (AMR) AF: 0.0188 AC: 287 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0228 AC: 110 AN: 4832

European-Finnish (FIN) AF: 0.0284 AC: 302 AN: 10618

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0153 AC: 1040 AN: 68026

Other (OTH) AF: 0.0189 AC: 40 AN: 2114

Alfa AF: 0.0127 Hom.: 5

Bravo AF: 0.0222

Asia WGS AF: 0.0180 AC: 63 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Benign:3

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

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:2

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 10, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jul 10, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.012
DANN	Benign	0.40
PhyloP100		-0.95
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61987277; hg19: chr14-64593207;