rs149978500

chr14-64220540-A-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.19964A>T(p.Gln6655Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00295 in 1,614,118 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 0.0019 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (7 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.720

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=0.0054953694).
• BP6: Variant 14-64220540-A-T is Benign according to our data. Variant chr14-64220540-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 281670.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=3}. Variant chr14-64220540-A-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00192 (293/152224) while in subpopulation NFE AF= 0.003 (204/68008). AF 95% confidence interval is 0.00266. There are 2 homozygotes in gnomad4. There are 126 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 293 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.19964A>T	p.Gln6655Leu	missense_variant	111/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.19964A>T	p.Gln6655Leu	missense_variant	111/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 293 AN: 152106 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000832

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00300

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00224 AC: 564 AN: 251454 Hom.: 0 AF XY: 0.00213 AC XY: 289 AN XY: 135908

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00280

Gnomad ASJ exome AF: 0.00595

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00298

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00306 AC: 4476 AN: 1461894 Hom.: 7 Cov.: 32 AF XY: 0.00310 AC XY: 2252 AN XY: 727248

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00259

Gnomad4 ASJ exome AF: 0.00562

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00101

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.00341

Gnomad4 OTH exome AF: 0.00351

GnomAD4 genome AF: 0.00192 AC: 293 AN: 152224 Hom.: 2 Cov.: 32 AF XY: 0.00169 AC XY: 126 AN XY: 74416

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000833

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00300

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00304 Hom.: 0

Bravo AF: 0.00222

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00222 AC: 270

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00365

EpiControl AF: 0.00474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 28, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	SYNE2: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

SYNE2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	8.8
Dann	Benign	0.61
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.77	T;T;T;T;T;T;T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.0055	T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	D;D;D;D;N;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Pathogenic	-5.8	D;.;D;D;D;D;.
REVEL	Benign	0.075
Sift	Benign	0.043	D;.;D;D;T;T;.
Sift4G	Uncertain	0.043	D;D;D;D;T;T;.
Polyphen		0.31	B;.;B;B;.;B;B
Vest4		0.38
MVP		0.52
MPC		0.14
ClinPred		0.059	T
GERP RS		2.4
Varity_R		0.20
gMVP		0.46

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: rs149978500; hg19: chr14-64687258; COSMIC: COSV99051080; COSMIC: COSV99051080;