chr14-64219489-A-G

Variant names:

• chr14-64219489-A-G
• rs915057
• NM_182914.3:c.19860+79A>G

Variant summary

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

The NM_182914.3(SYNE2):​c.19860+79A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.582 in 1,419,412 control chromosomes in the GnomAD database, including 245,907 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (34862 hom., cov: 32)
  • Exomes 𝑓: 0.57 (211045 hom.)
• Consequence: SYNE2 NM_182914.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.04
• Publications: 23 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=-0.94).
• BP6: Variant 14-64219489-A-G is Benign according to our data. Variant chr14-64219489-A-G is described in ClinVar as Benign. ClinVar VariationId is 1270010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.873 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.19860+79A>G		intron_variant	Intron 110 of 115	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.19860+79A>G		intron_variant	Intron 110 of 115	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.662 AC: 100603 AN: 151986 Hom.: 34811 Cov.: 32

Gnomad AFR AF: 0.880

Gnomad AMI AF: 0.782

Gnomad AMR AF: 0.564

Gnomad ASJ AF: 0.635

Gnomad EAS AF: 0.729

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.578

Gnomad MID AF: 0.561

Gnomad NFE AF: 0.572

Gnomad OTH AF: 0.640

GnomAD4 exome AF: 0.572 AC: 725127 AN: 1267308 Hom.: 211045 AF XY: 0.568 AC XY: 362141 AN XY: 637442

African (AFR) AF: 0.889 AC: 26555 AN: 29854

American (AMR) AF: 0.534 AC: 21873 AN: 40994

Ashkenazi Jewish (ASJ) AF: 0.634 AC: 15589 AN: 24592

East Asian (EAS) AF: 0.681 AC: 26192 AN: 38434

South Asian (SAS) AF: 0.484 AC: 38639 AN: 79868

European-Finnish (FIN) AF: 0.568 AC: 29320 AN: 51592

Middle Eastern (MID) AF: 0.595 AC: 2870 AN: 4824

European-Non Finnish (NFE) AF: 0.564 AC: 531749 AN: 943144

Other (OTH) AF: 0.599 AC: 32340 AN: 54006

GnomAD4 genome AF: 0.662 AC: 100709 AN: 152104 Hom.: 34862 Cov.: 32 AF XY: 0.657 AC XY: 48859 AN XY: 74346

African (AFR) AF: 0.881 AC: 36565 AN: 41516

American (AMR) AF: 0.564 AC: 8609 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.635 AC: 2205 AN: 3470

East Asian (EAS) AF: 0.728 AC: 3766 AN: 5170

South Asian (SAS) AF: 0.489 AC: 2360 AN: 4822

European-Finnish (FIN) AF: 0.578 AC: 6105 AN: 10564

Middle Eastern (MID) AF: 0.541 AC: 158 AN: 292

European-Non Finnish (NFE) AF: 0.572 AC: 38877 AN: 67972

Other (OTH) AF: 0.639 AC: 1351 AN: 2114

Alfa AF: 0.723 Hom.: 10216

Bravo AF: 0.675

Asia WGS AF: 0.622 AC: 2164 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.031
DANN	Benign	0.16
PhyloP100		-1.0
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: rs915057; hg19: chr14-64686207; COSMIC: COSV59958466;