14-64087370-G-A

Variant names:

• chr14-64087370-G-A
• rs77860632
• NM_182914.3:c.11485-301G>A

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.11485-301G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0348 in 551,250 control chromosomes in the GnomAD database, including 464 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (108 hom., cov: 32)
  • Exomes 𝑓: 0.036 (356 hom.)
• Consequence: SYNE2 NM_182914.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.272
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 14-64087370-G-A is Benign according to our data. Variant chr14-64087370-G-A is described in ClinVar as [Benign]. Clinvar id is 1291221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0621 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.11485-301G>A		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.11485-301G>A		intron_variant	Intron 57 of 115	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.0313 AC: 4762 AN: 151906 Hom.: 108 Cov.: 32

Gnomad AFR AF: 0.00837

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0655

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.0501

Gnomad SAS AF: 0.0277

Gnomad FIN AF: 0.0608

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.0333

Gnomad OTH AF: 0.0282

GnomAD2 exomes AF: 0.0378 AC: 8683 AN: 229610 AF XY: 0.0363

Gnomad AFR exome AF: 0.00837

Gnomad AMR exome AF: 0.0798

Gnomad ASJ exome AF: 0.0144

Gnomad EAS exome AF: 0.0485

Gnomad FIN exome AF: 0.0498

Gnomad NFE exome AF: 0.0304

Gnomad OTH exome AF: 0.0345

GnomAD4 exome AF: 0.0361 AC: 14408 AN: 399226 Hom.: 356 Cov.: 0 AF XY: 0.0355 AC XY: 8040 AN XY: 226326

African (AFR) AF: 0.00858 AC: 93 AN: 10836

American (AMR) AF: 0.0782 AC: 2442 AN: 31210

Ashkenazi Jewish (ASJ) AF: 0.0125 AC: 155 AN: 12404

East Asian (EAS) AF: 0.0500 AC: 807 AN: 16146

South Asian (SAS) AF: 0.0314 AC: 2019 AN: 64310

European-Finnish (FIN) AF: 0.0498 AC: 1553 AN: 31200

Middle Eastern (MID) AF: 0.0113 AC: 33 AN: 2918

European-Non Finnish (NFE) AF: 0.0317 AC: 6722 AN: 211774

Other (OTH) AF: 0.0317 AC: 584 AN: 18428

GnomAD4 genome AF: 0.0313 AC: 4762 AN: 152024 Hom.: 108 Cov.: 32 AF XY: 0.0333 AC XY: 2475 AN XY: 74300

African (AFR) AF: 0.00834 AC: 346 AN: 41484

American (AMR) AF: 0.0655 AC: 999 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 57 AN: 3468

East Asian (EAS) AF: 0.0500 AC: 259 AN: 5182

South Asian (SAS) AF: 0.0279 AC: 134 AN: 4806

European-Finnish (FIN) AF: 0.0608 AC: 641 AN: 10542

Middle Eastern (MID) AF: 0.00347 AC: 1 AN: 288

European-Non Finnish (NFE) AF: 0.0333 AC: 2266 AN: 67974

Other (OTH) AF: 0.0279 AC: 59 AN: 2114

Alfa AF: 0.0327 Hom.: 18

Bravo AF: 0.0299

Asia WGS AF: 0.0440 AC: 153 AN: 3462

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 15, 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	-0.90
CADD	Benign	0.33
DANN	Benign	0.67
PhyloP100		-0.27
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: rs77860632; hg19: chr14-64554088;