rs145218296

Positions:

• chr14-64113579-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_182914.3(SYNE2):​c.12840+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0242 in 1,596,276 control chromosomes in the GnomAD database, including 591 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (63 hom., cov: 32)
  • Exomes 𝑓: 0.024 (528 hom.)
• Consequence: SYNE2 NM_182914.3 splice_region, intron
• Scores: Splicing: ADA: 0.00002433
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.35

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=-0.84).
• BP6: Variant 14-64113579-T-C is Benign according to our data. Variant chr14-64113579-T-C is described in ClinVar as [Benign]. Clinvar id is 130468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64113579-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0222 (3378/152336) while in subpopulation NFE AF= 0.0305 (2077/68024). AF 95% confidence interval is 0.0294. There are 63 homozygotes in gnomad4. There are 1741 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3378 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.12840+8T>C		splice_region_variant, intron_variant		ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.12840+8T>C		splice_region_variant, intron_variant		1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.0222 AC: 3379 AN: 152218 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.00410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0266

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0615

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0305

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.0215 AC: 4682 AN: 218112 Hom.: 80 AF XY: 0.0212 AC XY: 2495 AN XY: 117548

Gnomad AFR exome AF: 0.00365

Gnomad AMR exome AF: 0.0168

Gnomad ASJ exome AF: 0.00995

Gnomad EAS exome AF: 0.000127

Gnomad SAS exome AF: 0.00381

Gnomad FIN exome AF: 0.0543

Gnomad NFE exome AF: 0.0285

Gnomad OTH exome AF: 0.0217

GnomAD4 exome AF: 0.0244 AC: 35250 AN: 1443940 Hom.: 528 Cov.: 32 AF XY: 0.0240 AC XY: 17176 AN XY: 716904

Gnomad4 AFR exome AF: 0.00322

Gnomad4 AMR exome AF: 0.0172

Gnomad4 ASJ exome AF: 0.00907

Gnomad4 EAS exome AF: 0.0000519

Gnomad4 SAS exome AF: 0.00386

Gnomad4 FIN exome AF: 0.0515

Gnomad4 NFE exome AF: 0.0271

Gnomad4 OTH exome AF: 0.0207

GnomAD4 genome AF: 0.0222 AC: 3378 AN: 152336 Hom.: 63 Cov.: 32 AF XY: 0.0234 AC XY: 1741 AN XY: 74494

Gnomad4 AFR AF: 0.00409

Gnomad4 AMR AF: 0.0265

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.0615

Gnomad4 NFE AF: 0.0305

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0263 Hom.: 23

Bravo AF: 0.0178

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 16, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2014	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 14, 2018

- -

SYNE2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.0080
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: rs145218296; hg19: chr14-64580297;