chr14-64098818-C-T

Variant names:

• chr14-64098818-C-T
• rs36007735
• NM_182914.3:c.12378C>T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_182914.3(SYNE2):​c.12378C>T​(p.Ser4126Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00677 in 1,613,616 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (47 hom.)
• Consequence: SYNE2 NM_182914.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.711

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 14-64098818-C-T is Benign according to our data. Variant chr14-64098818-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 198339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64098818-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.711 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00517 (787/152086) while in subpopulation NFE AF= 0.00784 (533/67988). AF 95% confidence interval is 0.00729. There are 5 homozygotes in gnomad4. There are 369 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 787 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.12378C>T	p.Ser4126Ser	synonymous_variant	Exon 63 of 116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.12378C>T	p.Ser4126Ser	synonymous_variant	Exon 63 of 116	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.00519 AC: 789 AN: 151968 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00155

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00596

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00782

Gnomad OTH AF: 0.00479

GnomAD3 exomes AF: 0.00546 AC: 1371 AN: 251134 Hom.: 5 AF XY: 0.00557 AC XY: 756 AN XY: 135710

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00179

Gnomad ASJ exome AF: 0.0161

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00243

Gnomad FIN exome AF: 0.00726

Gnomad NFE exome AF: 0.00752

Gnomad OTH exome AF: 0.00684

GnomAD4 exome AF: 0.00693 AC: 10135 AN: 1461530 Hom.: 47 Cov.: 31 AF XY: 0.00688 AC XY: 4999 AN XY: 727054

Gnomad4 AFR exome AF: 0.00146

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.0165

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00203

Gnomad4 FIN exome AF: 0.00801

Gnomad4 NFE exome AF: 0.00764

Gnomad4 OTH exome AF: 0.00633

GnomAD4 genome AF: 0.00517 AC: 787 AN: 152086 Hom.: 5 Cov.: 32 AF XY: 0.00496 AC XY: 369 AN XY: 74346

Gnomad4 AFR AF: 0.00154

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.0147

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00208

Gnomad4 FIN AF: 0.00596

Gnomad4 NFE AF: 0.00784

Gnomad4 OTH AF: 0.00474

Alfa AF: 0.00749 Hom.: 2

Bravo AF: 0.00469

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00829

EpiControl AF: 0.00831

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SYNE2: BP4, BP7, BS2 -

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Benign:2

Jan 13, 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:1

Nov 21, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SYNE2-related disorder Benign:1

Jun 03, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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	-0.46
CADD	Benign	0.89
DANN	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs36007735; hg19: chr14-64565536; COSMIC: COSV59967064; COSMIC: COSV59967064;