rs1152583

Variant names:

• chr14-64225659-C-A
• rs1152583
• ENST00000394768.6:n.10324C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000394768.6(SYNE2):​n.10324C>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 991,726 control chromosomes in the GnomAD database, including 16,711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (6633 hom., cov: 32)
  • Exomes 𝑓: 0.13 (10078 hom.)
• Consequence: SYNE2 ENST00000394768.6 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.00900
• 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 (BayesDel_noAF=-0.82).
• BP6: Variant 14-64225659-C-A is Benign according to our data. Variant chr14-64225659-C-A is described in ClinVar as Benign. ClinVar VariationId is 313673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.498 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.*133C>A		3_prime_UTR_variant	Exon 116 of 116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.*133C>A		3_prime_UTR_variant	Exon 116 of 116	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35397 AN: 152016 Hom.: 6624 Cov.: 32

Gnomad AFR AF: 0.504

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0990

Gnomad OTH AF: 0.204

GnomAD4 exome AF: 0.127 AC: 106760 AN: 839590 Hom.: 10078 Cov.: 11 AF XY: 0.128 AC XY: 54804 AN XY: 429634

African (AFR) AF: 0.508 AC: 10562 AN: 20808

American (AMR) AF: 0.128 AC: 4445 AN: 34720

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 3239 AN: 21538

East Asian (EAS) AF: 0.383 AC: 12551 AN: 32758

South Asian (SAS) AF: 0.152 AC: 10358 AN: 68092

European-Finnish (FIN) AF: 0.111 AC: 5101 AN: 45842

Middle Eastern (MID) AF: 0.153 AC: 600 AN: 3926

European-Non Finnish (NFE) AF: 0.0938 AC: 53730 AN: 572638

Other (OTH) AF: 0.157 AC: 6174 AN: 39268

GnomAD4 genome AF: 0.233 AC: 35450 AN: 152136 Hom.: 6633 Cov.: 32 AF XY: 0.233 AC XY: 17312 AN XY: 74372

African (AFR) AF: 0.504 AC: 20904 AN: 41474

American (AMR) AF: 0.161 AC: 2466 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 500 AN: 3470

East Asian (EAS) AF: 0.448 AC: 2310 AN: 5162

South Asian (SAS) AF: 0.162 AC: 781 AN: 4824

European-Finnish (FIN) AF: 0.117 AC: 1235 AN: 10598

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.0989 AC: 6728 AN: 68004

Other (OTH) AF: 0.205 AC: 432 AN: 2108

Alfa AF: 0.167 Hom.: 1736

Bravo AF: 0.248

Asia WGS AF: 0.287 AC: 995 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

- -

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.5
DANN	Benign	0.52
PhyloP100		-0.0090
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: rs1152583; hg19: chr14-64692377;