rs142660236

Variant names:

• chr14-64158626-T-C
• rs142660236
• NM_182914.3:c.15794T>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.15794T>C​(p.Val5265Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0139 in 1,613,822 control chromosomes in the GnomAD database, including 196 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (16 hom., cov: 32)
  • Exomes 𝑓: 0.014 (180 hom.)
• Consequence: SYNE2 NM_182914.3 missense, splice_region
• Scores: Splicing: ADA: 0.6095
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.81
• Publications: 9 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=0.0029333234).
• BP6: Variant 14-64158626-T-C is Benign according to our data. Variant chr14-64158626-T-C is described in ClinVar as Benign. ClinVar VariationId is 130481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0121 (1847/152276) while in subpopulation NFE AF = 0.0168 (1140/68022). AF 95% confidence interval is 0.016. There are 16 homozygotes in GnomAd4. There are 940 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1847 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182914.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	NM_182914.3	MANE Select	c.15794T>C	p.Val5265Ala	missense splice_region	Exon 86 of 116	NP_878918.2
	SYNE2	NM_015180.6		c.15794T>C	p.Val5265Ala	missense splice_region	Exon 86 of 115	NP_055995.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	ENST00000555002.6	TSL:1 MANE Select	c.15794T>C	p.Val5265Ala	missense splice_region	Exon 86 of 116	ENSP00000450831.2
	SYNE2	ENST00000344113.8	TSL:1	c.15794T>C	p.Val5265Ala	missense splice_region	Exon 86 of 115	ENSP00000341781.4
	SYNE2	ENST00000394768.6	TSL:1	n.5327T>C		splice_region non_coding_transcript_exon	Exon 34 of 63

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1849 AN: 152158 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.0429

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.0350

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.0138 AC: 3454 AN: 250958 AF XY: 0.0149

Gnomad AFR exome AF: 0.00222

Gnomad AMR exome AF: 0.0124

Gnomad ASJ exome AF: 0.0441

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0103

Gnomad NFE exome AF: 0.0158

Gnomad OTH exome AF: 0.0200

GnomAD4 exome AF: 0.0141 AC: 20596 AN: 1461546 Hom.: 180 Cov.: 32 AF XY: 0.0144 AC XY: 10492 AN XY: 727082

African (AFR) AF: 0.00287 AC: 96 AN: 33462

American (AMR) AF: 0.0130 AC: 582 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.0436 AC: 1140 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.0141 AC: 1217 AN: 86248

European-Finnish (FIN) AF: 0.00952 AC: 508 AN: 53386

Middle Eastern (MID) AF: 0.0349 AC: 201 AN: 5764

European-Non Finnish (NFE) AF: 0.0143 AC: 15900 AN: 1111796

Other (OTH) AF: 0.0157 AC: 951 AN: 60384

GnomAD4 genome AF: 0.0121 AC: 1847 AN: 152276 Hom.: 16 Cov.: 32 AF XY: 0.0126 AC XY: 940 AN XY: 74450

African (AFR) AF: 0.00286 AC: 119 AN: 41550

American (AMR) AF: 0.0141 AC: 215 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0429 AC: 149 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5184

South Asian (SAS) AF: 0.0139 AC: 67 AN: 4822

European-Finnish (FIN) AF: 0.0106 AC: 113 AN: 10618

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.0168 AC: 1140 AN: 68022

Other (OTH) AF: 0.0151 AC: 32 AN: 2114

Alfa AF: 0.0153 Hom.: 73

Bravo AF: 0.0117

TwinsUK AF: 0.0127 AC: 47

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0170 AC: 146

ExAC AF: 0.0134 AC: 1624

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0174

EpiControl AF: 0.0197

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 28, 2017

Genome Diagnostics Laboratory, University Medical Center Utrecht

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 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 Benign:2

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.069	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		4.8
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.085
Sift	Benign	0.031	D
Sift4G	Uncertain	0.052	T
Polyphen		0.41	B
Vest4		0.52
MPC		0.18
ClinPred		0.013	T
GERP RS		5.8
Varity_R		0.13
gMVP		0.20
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.61
dbscSNV1_RF	Benign	0.57
SpliceAI score (max)		0.020		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: rs142660236; hg19: chr14-64625344;