rs10137972

chr14-64091016-A-Cchr14-64091016-A-G

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.11944A>C(p.Asn3982His) variant causes a missense change. The variant allele was found at a frequency of 0.0609 in 1,613,786 control chromosomes in the GnomAD database, including 3,633 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N3982D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.088 (769 hom., cov: 33)
  • Exomes 𝑓: 0.058 (2864 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 6.09

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=0.0012866855).
• BP6: Variant 14-64091016-A-C is Benign according to our data. Variant chr14-64091016-A-C is described in ClinVar as [Benign]. Clinvar id is 130461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64091016-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.11944A>C	p.Asn3982His	missense_variant	60/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.11944A>C	p.Asn3982His	missense_variant	60/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.0875 AC: 13309 AN: 152148 Hom.: 761 Cov.: 33

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.0586

Gnomad ASJ AF: 0.0769

Gnomad EAS AF: 0.0721

Gnomad SAS AF: 0.0410

Gnomad FIN AF: 0.0760

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0560

Gnomad OTH AF: 0.0911

GnomAD3 exomes AF: 0.0639 AC: 16030 AN: 250994 Hom.: 627 AF XY: 0.0621 AC XY: 8424 AN XY: 135670

Gnomad AFR exome AF: 0.156

Gnomad AMR exome AF: 0.0412

Gnomad ASJ exome AF: 0.0764

Gnomad EAS exome AF: 0.0818

Gnomad SAS exome AF: 0.0355

Gnomad FIN exome AF: 0.0744

Gnomad NFE exome AF: 0.0588

Gnomad OTH exome AF: 0.0718

GnomAD4 exome AF: 0.0581 AC: 84913 AN: 1461520 Hom.: 2864 Cov.: 31 AF XY: 0.0573 AC XY: 41639 AN XY: 727084

Gnomad4 AFR exome AF: 0.168

Gnomad4 AMR exome AF: 0.0451

Gnomad4 ASJ exome AF: 0.0722

Gnomad4 EAS exome AF: 0.0587

Gnomad4 SAS exome AF: 0.0341

Gnomad4 FIN exome AF: 0.0703

Gnomad4 NFE exome AF: 0.0557

Gnomad4 OTH exome AF: 0.0658

GnomAD4 genome AF: 0.0877 AC: 13357 AN: 152266 Hom.: 769 Cov.: 33 AF XY: 0.0881 AC XY: 6559 AN XY: 74466

Gnomad4 AFR AF: 0.160

Gnomad4 AMR AF: 0.0585

Gnomad4 ASJ AF: 0.0769

Gnomad4 EAS AF: 0.0723

Gnomad4 SAS AF: 0.0408

Gnomad4 FIN AF: 0.0760

Gnomad4 NFE AF: 0.0560

Gnomad4 OTH AF: 0.0906

Alfa AF: 0.0595 Hom.: 365

Bravo AF: 0.0912

TwinsUK AF: 0.0520 AC: 193

ALSPAC AF: 0.0581 AC: 224

ESP6500AA AF: 0.146 AC: 645

ESP6500EA AF: 0.0555 AC: 477

ExAC AF: 0.0655 AC: 7948

Asia WGS AF: 0.0790 AC: 273 AN: 3478

EpiCase AF: 0.0633

EpiControl AF: 0.0636

ClinVar

Significance: 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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 15, 2013

- -

SYNE2-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 05, 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

GeneDx

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	21
Dann	Benign	0.86
Eigen	Benign	0.14
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
MetaRNN	Benign	0.0013	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;.;M;.;.
MutationTaster	Benign	0.83	P;P;P;P;P;P;P
PrimateAI	Benign	0.47	T
PROVEAN	Benign	1.1	N;.;N;N;N
REVEL	Benign	0.10
Sift	Benign	1.0	T;.;T;T;T
Sift4G	Uncertain	0.050	T;T;T;T;T
Polyphen		0.96	D;.;P;.;.
Vest4		0.22
MPC		0.31
ClinPred		0.043	T
GERP RS		3.4
Varity_R		0.042
gMVP		0.13

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: rs10137972; hg19: chr14-64557734; COSMIC: COSV59958750; COSMIC: COSV59958750;