rs1255953

Variant names:

• chr14-64084970-C-T
• rs1255953
• NM_182914.3:c.11485-2701C>T

Variant summary

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

The NM_182914.3(SYNE2):​c.11485-2701C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 702,064 control chromosomes in the GnomAD database, including 226,313 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 0.73 (42677 hom., cov: 32)
  • Exomes 𝑓: 0.81 (183636 hom.)
• Consequence: SYNE2 NM_182914.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.196
• Publications: 10 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 (MetaRNN=8.773652E-7).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.846 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.11485-2701C>T		intron_variant	Intron 57 of 115	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.11485-2701C>T		intron_variant	Intron 57 of 115	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.733 AC: 111430 AN: 152068 Hom.: 42668 Cov.: 32

Gnomad AFR AF: 0.491

Gnomad AMI AF: 0.845

Gnomad AMR AF: 0.774

Gnomad ASJ AF: 0.737

Gnomad EAS AF: 0.775

Gnomad SAS AF: 0.770

Gnomad FIN AF: 0.807

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.851

Gnomad OTH AF: 0.741

GnomAD2 exomes AF: 0.793 AC: 101450 AN: 128008 AF XY: 0.796

Gnomad AFR exome AF: 0.480

Gnomad AMR exome AF: 0.812

Gnomad ASJ exome AF: 0.731

Gnomad EAS exome AF: 0.753

Gnomad FIN exome AF: 0.815

Gnomad NFE exome AF: 0.847

Gnomad OTH exome AF: 0.777

GnomAD4 exome AF: 0.813 AC: 447277 AN: 549878 Hom.: 183636 Cov.: 0 AF XY: 0.814 AC XY: 242174 AN XY: 297686

African (AFR) AF: 0.481 AC: 7604 AN: 15794

American (AMR) AF: 0.804 AC: 27900 AN: 34696

Ashkenazi Jewish (ASJ) AF: 0.731 AC: 14640 AN: 20018

East Asian (EAS) AF: 0.780 AC: 25025 AN: 32092

South Asian (SAS) AF: 0.783 AC: 49119 AN: 62740

European-Finnish (FIN) AF: 0.822 AC: 27257 AN: 33178

Middle Eastern (MID) AF: 0.789 AC: 3206 AN: 4064

European-Non Finnish (NFE) AF: 0.847 AC: 268346 AN: 316722

Other (OTH) AF: 0.791 AC: 24180 AN: 30574

GnomAD4 genome AF: 0.732 AC: 111467 AN: 152186 Hom.: 42677 Cov.: 32 AF XY: 0.731 AC XY: 54388 AN XY: 74396

African (AFR) AF: 0.490 AC: 20328 AN: 41484

American (AMR) AF: 0.774 AC: 11840 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.737 AC: 2560 AN: 3472

East Asian (EAS) AF: 0.774 AC: 4013 AN: 5182

South Asian (SAS) AF: 0.771 AC: 3717 AN: 4820

European-Finnish (FIN) AF: 0.807 AC: 8554 AN: 10598

Middle Eastern (MID) AF: 0.728 AC: 214 AN: 294

European-Non Finnish (NFE) AF: 0.851 AC: 57911 AN: 68020

Other (OTH) AF: 0.740 AC: 1561 AN: 2110

Alfa AF: 0.805 Hom.: 152882

Bravo AF: 0.720

TwinsUK AF: 0.861 AC: 3194

ALSPAC AF: 0.852 AC: 3282

ExAC AF: 0.738 AC: 9865

Asia WGS AF: 0.744 AC: 2589 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	3.3
DANN	Benign	0.70
Eigen	Benign	-0.80
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	8.8e-7	T
MetaSVM	Benign	-0.98	T
PhyloP100		-0.20
Sift4G	Benign	0.22	T
Vest4		0.014
ClinPred		0.00010	T
GERP RS		-1.5
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: rs1255953; hg19: chr14-64551688;