14-64225912-G-C

Variant names:

• chr14-64225912-G-C
• rs1152582
• ENST00000394768.6:n.10577G>C

Variant summary

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

The ENST00000394768.6(SYNE2):​n.10577G>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.606 in 421,840 control chromosomes in the GnomAD database, including 80,409 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (34299 hom., cov: 31)
  • Exomes 𝑓: 0.58 (46110 hom.)
• Consequence: SYNE2 ENST00000394768.6 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.766
• 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=-0.89).
• BP6: Variant 14-64225912-G-C is Benign according to our data. Variant chr14-64225912-G-C is described in ClinVar as Benign. ClinVar VariationId is 313681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.872 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.*386G>C		3_prime_UTR_variant	Exon 116 of 116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.*386G>C		3_prime_UTR_variant	Exon 116 of 116	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.656 AC: 99718 AN: 151944 Hom.: 34245 Cov.: 31

Gnomad AFR AF: 0.879

Gnomad AMI AF: 0.777

Gnomad AMR AF: 0.561

Gnomad ASJ AF: 0.636

Gnomad EAS AF: 0.693

Gnomad SAS AF: 0.506

Gnomad FIN AF: 0.581

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.562

Gnomad OTH AF: 0.637

GnomAD4 exome AF: 0.577 AC: 155692 AN: 269778 Hom.: 46110 Cov.: 0 AF XY: 0.573 AC XY: 79017 AN XY: 137916

African (AFR) AF: 0.884 AC: 8433 AN: 9542

American (AMR) AF: 0.543 AC: 5872 AN: 10822

Ashkenazi Jewish (ASJ) AF: 0.633 AC: 5983 AN: 9446

East Asian (EAS) AF: 0.633 AC: 12545 AN: 19808

South Asian (SAS) AF: 0.495 AC: 9961 AN: 20138

European-Finnish (FIN) AF: 0.561 AC: 8615 AN: 15362

Middle Eastern (MID) AF: 0.614 AC: 779 AN: 1268

European-Non Finnish (NFE) AF: 0.561 AC: 93345 AN: 166444

Other (OTH) AF: 0.599 AC: 10159 AN: 16948

GnomAD4 genome AF: 0.656 AC: 99825 AN: 152062 Hom.: 34299 Cov.: 31 AF XY: 0.652 AC XY: 48473 AN XY: 74312

African (AFR) AF: 0.879 AC: 36498 AN: 41516

American (AMR) AF: 0.561 AC: 8569 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.636 AC: 2207 AN: 3472

East Asian (EAS) AF: 0.693 AC: 3583 AN: 5168

South Asian (SAS) AF: 0.505 AC: 2424 AN: 4800

European-Finnish (FIN) AF: 0.581 AC: 6129 AN: 10552

Middle Eastern (MID) AF: 0.548 AC: 161 AN: 294

European-Non Finnish (NFE) AF: 0.562 AC: 38199 AN: 67950

Other (OTH) AF: 0.637 AC: 1346 AN: 2114

Alfa AF: 0.608 Hom.: 3461

Bravo AF: 0.669

Asia WGS AF: 0.609 AC: 2119 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.3
DANN	Benign	0.64
PhyloP100		-0.77
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: rs1152582; hg19: chr14-64692630;