rs1152583

Variant names:

• chr14-64225659-C-A
• rs1152583
• NM_182914.3:c.*133C>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182914.3(SYNE2):​c.*133C>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 0.143 in 991,726 control chromosomes in the GnomAD database, including 16,711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (6633 hom., cov: 32)
  • Exomes 𝑓: 0.13 (10078 hom.)
• Consequence: SYNE2 NM_182914.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.00900

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 14-64225659-C-A is Benign according to our data. Variant chr14-64225659-C-A is described in ClinVar as [Benign]. Clinvar id is 313673.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.498 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.*133C>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.*133C>A		3_prime_UTR_variant	Exon 116 of 116	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.233 AC: 35397 AN: 152016 Hom.: 6624 Cov.: 32

Gnomad AFR AF: 0.504

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.163

Gnomad FIN AF: 0.117

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0990

Gnomad OTH AF: 0.204

GnomAD4 exome AF: 0.127 AC: 106760 AN: 839590 Hom.: 10078 Cov.: 11 AF XY: 0.128 AC XY: 54804 AN XY: 429634

Gnomad4 AFR exome AF: 0.508

Gnomad4 AMR exome AF: 0.128

Gnomad4 ASJ exome AF: 0.150

Gnomad4 EAS exome AF: 0.383

Gnomad4 SAS exome AF: 0.152

Gnomad4 FIN exome AF: 0.111

Gnomad4 NFE exome AF: 0.0938

Gnomad4 OTH exome AF: 0.157

GnomAD4 genome AF: 0.233 AC: 35450 AN: 152136 Hom.: 6633 Cov.: 32 AF XY: 0.233 AC XY: 17312 AN XY: 74372

Gnomad4 AFR AF: 0.504

Gnomad4 AMR AF: 0.161

Gnomad4 ASJ AF: 0.144

Gnomad4 EAS AF: 0.448

Gnomad4 SAS AF: 0.162

Gnomad4 FIN AF: 0.117

Gnomad4 NFE AF: 0.0989

Gnomad4 OTH AF: 0.205

Alfa AF: 0.163 Hom.: 1402

Bravo AF: 0.248

Asia WGS AF: 0.287 AC: 995 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 12, 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	-0.82
CADD	Benign	1.5
DANN	Benign	0.52

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: rs1152583; hg19: chr14-64692377;