NM_182914.3:c.13917+494G>A

Variant names:

• chr14-64127301-G-A
• rs57018718
• NM_182914.3:c.13917+494G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_182914.3(SYNE2):​c.13917+494G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0678 in 151,938 control chromosomes in the GnomAD database, including 433 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.068 (433 hom., cov: 32)
• Consequence: SYNE2 NM_182914.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.72
• Publications: 1 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.06).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.13917+494G>A		intron_variant	Intron 73 of 115	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.13917+494G>A		intron_variant	Intron 73 of 115	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.0679 AC: 10302 AN: 151820 Hom.: 436 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0729

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.0990

Gnomad FIN AF: 0.0197

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0383

Gnomad OTH AF: 0.0746

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0678 AC: 10302 AN: 151938 Hom.: 433 Cov.: 32 AF XY: 0.0686 AC XY: 5093 AN XY: 74266

African (AFR) AF: 0.112 AC: 4654 AN: 41420

American (AMR) AF: 0.0728 AC: 1110 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 379 AN: 3470

East Asian (EAS) AF: 0.133 AC: 689 AN: 5166

South Asian (SAS) AF: 0.0981 AC: 471 AN: 4802

European-Finnish (FIN) AF: 0.0197 AC: 208 AN: 10550

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0383 AC: 2605 AN: 67960

Other (OTH) AF: 0.0743 AC: 157 AN: 2112

Alfa AF: 0.0279 Hom.: 21

Bravo AF: 0.0720

Asia WGS AF: 0.102 AC: 355 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.42
DANN	Benign	0.56
PhyloP100		-1.7
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: rs57018718; hg19: chr14-64594019;