chr14-64214475-C-T

Variant names:

• chr14-64214475-C-T
• rs1152590
• NM_182914.3:c.19333+5C>T

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.19333+5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 1,607,706 control chromosomes in the GnomAD database, including 141,801 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 0.50 (21508 hom., cov: 31)
  • Exomes 𝑓: 0.40 (120293 hom.)
• Consequence: SYNE2 NM_182914.3 splice_region, intron
• Scores: Splicing: ADA: 0.00002039
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.20

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=-0.9).
• BP6: Variant 14-64214475-C-T is Benign according to our data. Variant chr14-64214475-C-T is described in ClinVar as [Benign]. Clinvar id is 130489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64214475-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.75 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.19333+5C>T		splice_region_variant, intron_variant	Intron 106 of 115	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.19333+5C>T		splice_region_variant, intron_variant	Intron 106 of 115	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.503 AC: 76403 AN: 151780 Hom.: 21470 Cov.: 31

Gnomad AFR AF: 0.757

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.424

Gnomad ASJ AF: 0.486

Gnomad EAS AF: 0.695

Gnomad SAS AF: 0.448

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.379

Gnomad OTH AF: 0.491

GnomAD3 exomes AF: 0.441 AC: 105741 AN: 239802 Hom.: 24862 AF XY: 0.432 AC XY: 56284 AN XY: 130174

Gnomad AFR exome AF: 0.764

Gnomad AMR exome AF: 0.389

Gnomad ASJ exome AF: 0.488

Gnomad EAS exome AF: 0.695

Gnomad SAS exome AF: 0.428

Gnomad FIN exome AF: 0.375

Gnomad NFE exome AF: 0.381

Gnomad OTH exome AF: 0.410

GnomAD4 exome AF: 0.398 AC: 579038 AN: 1455808 Hom.: 120293 Cov.: 38 AF XY: 0.397 AC XY: 287683 AN XY: 724044

Gnomad4 AFR exome AF: 0.768

Gnomad4 AMR exome AF: 0.393

Gnomad4 ASJ exome AF: 0.486

Gnomad4 EAS exome AF: 0.650

Gnomad4 SAS exome AF: 0.427

Gnomad4 FIN exome AF: 0.366

Gnomad4 NFE exome AF: 0.373

Gnomad4 OTH exome AF: 0.435

GnomAD4 genome AF: 0.504 AC: 76493 AN: 151898 Hom.: 21508 Cov.: 31 AF XY: 0.501 AC XY: 37161 AN XY: 74222

Gnomad4 AFR AF: 0.758

Gnomad4 AMR AF: 0.424

Gnomad4 ASJ AF: 0.486

Gnomad4 EAS AF: 0.695

Gnomad4 SAS AF: 0.447

Gnomad4 FIN AF: 0.366

Gnomad4 NFE AF: 0.379

Gnomad4 OTH AF: 0.487

Alfa AF: 0.424 Hom.: 5110

Bravo AF: 0.520

Asia WGS AF: 0.549 AC: 1907 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Benign:4

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

not specified Benign:3

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 18, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.66
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
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: rs1152590; hg19: chr14-64681193;