rs7229

Variant names:

• chr14-64226107-G-A
• rs7229
• ENST00000394768.6:n.10772G>A

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.10772G>A 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 0.656 in 157,060 control chromosomes in the GnomAD database, including 35,459 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (34734 hom., cov: 32)
  • Exomes 𝑓: 0.53 (725 hom.)
• Consequence: SYNE2 ENST00000394768.6 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0870
• Publications: 21 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=-0.69).
• BP6: Variant 14-64226107-G-A is Benign according to our data. Variant chr14-64226107-G-A is described in ClinVar as [Benign]. Clinvar id is 313684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.885 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.*581G>A		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.*581G>A		3_prime_UTR_variant	Exon 116 of 116	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.659 AC: 100189 AN: 151942 Hom.: 34680 Cov.: 32

Gnomad AFR AF: 0.892

Gnomad AMI AF: 0.779

Gnomad AMR AF: 0.562

Gnomad ASJ AF: 0.636

Gnomad EAS AF: 0.686

Gnomad SAS AF: 0.500

Gnomad FIN AF: 0.580

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.562

Gnomad OTH AF: 0.640

GnomAD4 exome AF: 0.533 AC: 2663 AN: 5000 Hom.: 725 Cov.: 0 AF XY: 0.527 AC XY: 1345 AN XY: 2550

African (AFR) AF: 0.913 AC: 42 AN: 46

American (AMR) AF: 0.486 AC: 557 AN: 1146

Ashkenazi Jewish (ASJ) AF: 0.632 AC: 24 AN: 38

East Asian (EAS) AF: 0.627 AC: 84 AN: 134

South Asian (SAS) AF: 0.463 AC: 151 AN: 326

European-Finnish (FIN) AF: 0.551 AC: 258 AN: 468

Middle Eastern (MID) AF: 0.500 AC: 1 AN: 2

European-Non Finnish (NFE) AF: 0.542 AC: 1434 AN: 2648

Other (OTH) AF: 0.583 AC: 112 AN: 192

GnomAD4 genome AF: 0.660 AC: 100297 AN: 152060 Hom.: 34734 Cov.: 32 AF XY: 0.656 AC XY: 48708 AN XY: 74306

African (AFR) AF: 0.892 AC: 37060 AN: 41524

American (AMR) AF: 0.562 AC: 8585 AN: 15280

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

East Asian (EAS) AF: 0.686 AC: 3544 AN: 5166

South Asian (SAS) AF: 0.500 AC: 2402 AN: 4808

European-Finnish (FIN) AF: 0.580 AC: 6115 AN: 10540

Middle Eastern (MID) AF: 0.541 AC: 159 AN: 294

European-Non Finnish (NFE) AF: 0.562 AC: 38163 AN: 67952

Other (OTH) AF: 0.640 AC: 1353 AN: 2114

Alfa AF: 0.587 Hom.: 66223

Bravo AF: 0.672

Asia WGS AF: 0.609 AC: 2115 AN: 3476

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	-0.69
CADD	Benign	3.5
DANN	Benign	0.81
PhyloP100		0.087
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: rs7229; hg19: chr14-64692825;