rs150955173

chr14-64216260-C-T

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.19415C>T(p.Ser6472Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00295 in 1,614,206 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S6472S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0023 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (12 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.43

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 (MetaRNN=0.0041516125).
• BP6: Variant 14-64216260-C-T is Benign according to our data. Variant chr14-64216260-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 282189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64216260-C-T is described in Lovd as [Likely_benign]. Variant chr14-64216260-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00227 (346/152322) while in subpopulation NFE AF= 0.00319 (217/68036). AF 95% confidence interval is 0.00284. There are 2 homozygotes in gnomad4. There are 179 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 346 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.19415C>T	p.Ser6472Leu	missense_variant	108/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.19415C>T	p.Ser6472Leu	missense_variant	108/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.00227 AC: 346 AN: 152204 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00660

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00319

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00249 AC: 625 AN: 251460 Hom.: 4 AF XY: 0.00258 AC XY: 351 AN XY: 135910

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00188

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00712

Gnomad NFE exome AF: 0.00353

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00302 AC: 4413 AN: 1461884 Hom.: 12 Cov.: 31 AF XY: 0.00298 AC XY: 2170 AN XY: 727244

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00184

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00835

Gnomad4 NFE exome AF: 0.00337

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.00227 AC: 346 AN: 152322 Hom.: 2 Cov.: 32 AF XY: 0.00240 AC XY: 179 AN XY: 74484

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.000866

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00660

Gnomad4 NFE AF: 0.00319

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00296 Hom.: 0

Bravo AF: 0.00170

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00259 AC: 314

EpiCase AF: 0.00273

EpiControl AF: 0.00290

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jul 30, 2015

- -

SYNE2-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 21, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2023

SYNE2: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Pathogenic	0.21
Cadd	Uncertain	25
Dann	Uncertain	0.98
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.0042	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.12	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.92	N;.;N;N;N;.;D
REVEL	Benign	0.17
Sift	Benign	0.26	T;.;T;T;T;.;T
Sift4G	Benign	0.12	T;D;D;D;T;.;T
Polyphen		0.97	D;.;P;D;.;.;D
Vest4		0.52
MVP		0.67
MPC		0.23
ClinPred		0.052	T
GERP RS		5.3
Varity_R		0.11
gMVP		0.30

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: rs150955173; hg19: chr14-64682978; COSMIC: COSV59947759; COSMIC: COSV59947759;