rs17101661

Variant names:

• chr14-64097962-G-A
• rs17101661
• NM_182914.3:c.12122G>A

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.12122G>A​(p.Arg4041His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,614,186 control chromosomes in the GnomAD database, including 211 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4041C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.017 (35 hom., cov: 32)
  • Exomes 𝑓: 0.014 (176 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.98
• Publications: 11 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=0.0019463599).
• BP6: Variant 14-64097962-G-A is Benign according to our data. Variant chr14-64097962-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130465.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 = 0.0175 (2661/152324) while in subpopulation AFR AF = 0.0281 (1167/41568). AF 95% confidence interval is 0.0267. There are 35 homozygotes in GnomAd4. There are 1250 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2661 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.12122G>A	p.Arg4041His	missense	Exon 62 of 116	NP_878918.2
	SYNE2	NM_015180.6		c.12122G>A	p.Arg4041His	missense	Exon 62 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.12122G>A	p.Arg4041His	missense	Exon 62 of 116	ENSP00000450831.2
	SYNE2	ENST00000344113.8	TSL:1	c.12122G>A	p.Arg4041His	missense	Exon 62 of 115	ENSP00000341781.4
	SYNE2	ENST00000394768.6	TSL:1	n.1655G>A		non_coding_transcript_exon	Exon 10 of 63

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2660 AN: 152206 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0151

Gnomad ASJ AF: 0.0401

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0145

Gnomad OTH AF: 0.0253

GnomAD2 exomes AF: 0.0124 AC: 3113 AN: 251440 AF XY: 0.0121

Gnomad AFR exome AF: 0.0260

Gnomad AMR exome AF: 0.0128

Gnomad ASJ exome AF: 0.0386

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00152

Gnomad NFE exome AF: 0.0143

Gnomad OTH exome AF: 0.0205

GnomAD4 exome AF: 0.0140 AC: 20456 AN: 1461862 Hom.: 176 Cov.: 31 AF XY: 0.0137 AC XY: 9978 AN XY: 727238

African (AFR) AF: 0.0284 AC: 950 AN: 33478

American (AMR) AF: 0.0141 AC: 632 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0370 AC: 966 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00235 AC: 203 AN: 86258

European-Finnish (FIN) AF: 0.00154 AC: 82 AN: 53420

Middle Eastern (MID) AF: 0.0168 AC: 97 AN: 5768

European-Non Finnish (NFE) AF: 0.0149 AC: 16581 AN: 1111984

Other (OTH) AF: 0.0156 AC: 943 AN: 60396

GnomAD4 genome AF: 0.0175 AC: 2661 AN: 152324 Hom.: 35 Cov.: 32 AF XY: 0.0168 AC XY: 1250 AN XY: 74488

African (AFR) AF: 0.0281 AC: 1167 AN: 41568

American (AMR) AF: 0.0151 AC: 231 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0401 AC: 139 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4834

European-Finnish (FIN) AF: 0.00160 AC: 17 AN: 10618

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0145 AC: 989 AN: 68030

Other (OTH) AF: 0.0251 AC: 53 AN: 2114

Alfa AF: 0.0167 Hom.: 82

Bravo AF: 0.0197

TwinsUK AF: 0.0189 AC: 70

ALSPAC AF: 0.0200 AC: 77

ESP6500AA AF: 0.0238 AC: 105

ESP6500EA AF: 0.0162 AC: 139

ExAC AF: 0.0120 AC: 1461

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0163

EpiControl AF: 0.0164

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 12, 2017

Athena Diagnostics

Significance: 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

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

Jan 31, 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.

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.20
DANN	Benign	0.88
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0089	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	N
PhyloP100		-3.0
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.042
Sift	Benign	0.17	T
Sift4G	Benign	0.13	T
Polyphen		0.17	B
Vest4		0.053
MPC		0.084
ClinPred		0.00056	T
GERP RS		-6.1
Varity_R		0.013
gMVP		0.15
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs17101661; hg19: chr14-64564680;