14-64212580-T-G

Variant names:

• chr14-64212580-T-G
• rs8021944
• NM_182914.3:c.18862-231T>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_182914.3(SYNE2):​c.18862-231T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0552 in 152,320 control chromosomes in the GnomAD database, including 323 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.055 (323 hom., cov: 33)
• Consequence: SYNE2 NM_182914.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.993
• Publications: 3 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 14-64212580-T-G is Benign according to our data. Variant chr14-64212580-T-G is described in ClinVar as Benign. ClinVar VariationId is 1259964.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0772 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.18862-231T>G		intron_variant	Intron 104 of 115	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.18862-231T>G		intron_variant	Intron 104 of 115	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.0552 AC: 8396 AN: 152202 Hom.: 323 Cov.: 33

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.0998

Gnomad AMR AF: 0.0611

Gnomad ASJ AF: 0.0591

Gnomad EAS AF: 0.00480

Gnomad SAS AF: 0.0255

Gnomad FIN AF: 0.0929

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0790

Gnomad OTH AF: 0.0521

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

GnomAD4 genome AF: 0.0552 AC: 8401 AN: 152320 Hom.: 323 Cov.: 33 AF XY: 0.0541 AC XY: 4026 AN XY: 74476

African (AFR) AF: 0.0132 AC: 548 AN: 41576

American (AMR) AF: 0.0614 AC: 939 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0591 AC: 205 AN: 3470

East Asian (EAS) AF: 0.00482 AC: 25 AN: 5192

South Asian (SAS) AF: 0.0255 AC: 123 AN: 4826

European-Finnish (FIN) AF: 0.0929 AC: 986 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0790 AC: 5374 AN: 68024

Other (OTH) AF: 0.0516 AC: 109 AN: 2114

Alfa AF: 0.0320 Hom.: 23

Bravo AF: 0.0533

Asia WGS AF: 0.0200 AC: 69 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.21
DANN	Benign	0.68
PhyloP100		-0.99
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: rs8021944; hg19: chr14-64679298;