rs7229

Positions:

• chr14-64226107-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_182914.3(SYNE2):​c.*581G>A variant causes a 3 prime UTR 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 NM_182914.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0870

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]

ACMG classification

Verdict is Benign. Variant got -14 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_single_submitter, 1 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/exons	MANE	UniProt
SYNE2	NM_182914.3	c.*581G>A		3_prime_UTR_variant	116/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.*581G>A		3_prime_UTR_variant	116/116	1	NM_182914.3	P4

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

Gnomad4 AFR exome AF: 0.913

Gnomad4 AMR exome AF: 0.486

Gnomad4 ASJ exome AF: 0.632

Gnomad4 EAS exome AF: 0.627

Gnomad4 SAS exome AF: 0.463

Gnomad4 FIN exome AF: 0.551

Gnomad4 NFE exome AF: 0.542

Gnomad4 OTH exome AF: 0.583

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

Gnomad4 AFR AF: 0.892

Gnomad4 AMR AF: 0.562

Gnomad4 ASJ AF: 0.636

Gnomad4 EAS AF: 0.686

Gnomad4 SAS AF: 0.500

Gnomad4 FIN AF: 0.580

Gnomad4 NFE AF: 0.562

Gnomad4 OTH AF: 0.640

Alfa AF: 0.581 Hom.: 42410

Bravo AF: 0.672

Asia WGS AF: 0.609 AC: 2115 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs7229; hg19: chr14-64692825;