rs141741640

Variant names:

• chr14-64214272-C-T
• rs141741640
• NM_182914.3:c.19135C>T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_182914.3(SYNE2):​c.19135C>T​(p.Arg6379Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,613,902 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (5 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8 O:1
• Conservation: PhyloP100: 0.993

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015034795).
• BP6: Variant 14-64214272-C-T is Benign according to our data. Variant chr14-64214272-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193779.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=1, Uncertain_significance=1, not_provided=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0013 (198/152008) while in subpopulation NFE AF= 0.00247 (168/67988). AF 95% confidence interval is 0.00217. There are 0 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 198 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.19135C>T	p.Arg6379Cys	missense_variant	Exon 106 of 116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.19135C>T	p.Arg6379Cys	missense_variant	Exon 106 of 116	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.00130 AC: 198 AN: 151892 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000339

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000395

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000757

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00247

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00132 AC: 333 AN: 251488 Hom.: 0 AF XY: 0.00133 AC XY: 181 AN XY: 135920

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000598

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.00228

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00188 AC: 2744 AN: 1461894 Hom.: 5 Cov.: 38 AF XY: 0.00178 AC XY: 1292 AN XY: 727248

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000402

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00155

Gnomad4 NFE exome AF: 0.00230

Gnomad4 OTH exome AF: 0.000861

GnomAD4 genome AF: 0.00130 AC: 198 AN: 152008 Hom.: 0 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74292

Gnomad4 AFR AF: 0.000338

Gnomad4 AMR AF: 0.000394

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000757

Gnomad4 NFE AF: 0.00247

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00195 Hom.: 2

Bravo AF: 0.00127

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00302 AC: 26

ExAC AF: 0.00128 AC: 155

EpiCase AF: 0.00240

EpiControl AF: 0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Benign:3 Other:1

-

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Likely benign and reported on 07-24-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 05, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely 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 Uncertain:1 Benign:2

Apr 18, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.19135C>T (p.R6379C) alteration is located in exon 106 (coding exon 105) of the SYNE2 gene. This alteration results from a C to T substitution at nucleotide position 19135, causing the arginine (R) at amino acid position 6379 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Aug 25, 2015

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 15, 2024

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SYNE2: BP4, BS2 -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

SYNE2-related disorder Benign:1

Jan 07, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Benign	0.61
DEOGEN2	Benign	0.096	.;T;T;T;T;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	D;D;D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.015	T;T;T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	0.90	L;.;L;.;.;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Pathogenic	-4.4	D;.;D;D;D;.;D
REVEL	Benign	0.083
Sift	Uncertain	0.024	D;.;D;D;D;.;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;.;D
Polyphen		0.99	D;.;D;B;.;.;D
Vest4		0.28
MVP		0.52
MPC		0.063
ClinPred		0.067	T
GERP RS		3.5
Varity_R		0.13
gMVP		0.14

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: rs141741640; hg19: chr14-64680990;