rs2792205

Positions:

• chr14-64093373-T-C

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.12001T>C​(p.Trp4001Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0727 in 1,612,466 control chromosomes in the GnomAD database, including 5,112 homozygotes. In-silico tool predicts 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. W4001Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.089 (676 hom., cov: 32)
  • Exomes 𝑓: 0.071 (4436 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.57

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=0.0012952387).
• BP6: Variant 14-64093373-T-C is Benign according to our data. Variant chr14-64093373-T-C is described in ClinVar as [Benign]. Clinvar id is 130462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64093373-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.12001T>C	p.Trp4001Arg	missense_variant	61/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.12001T>C	p.Trp4001Arg	missense_variant	61/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.0893 AC: 13582 AN: 152116 Hom.: 676 Cov.: 32

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0799

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.0569

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0628

Gnomad OTH AF: 0.0963

GnomAD3 exomes AF: 0.0859 AC: 21585 AN: 251362 Hom.: 1152 AF XY: 0.0879 AC XY: 11945 AN XY: 135862

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.0486

Gnomad ASJ exome AF: 0.181

Gnomad EAS exome AF: 0.118

Gnomad SAS exome AF: 0.142

Gnomad FIN exome AF: 0.0583

Gnomad NFE exome AF: 0.0664

Gnomad OTH exome AF: 0.0992

GnomAD4 exome AF: 0.0710 AC: 103713 AN: 1460232 Hom.: 4436 Cov.: 32 AF XY: 0.0735 AC XY: 53379 AN XY: 726496

Gnomad4 AFR exome AF: 0.135

Gnomad4 AMR exome AF: 0.0523

Gnomad4 ASJ exome AF: 0.185

Gnomad4 EAS exome AF: 0.115

Gnomad4 SAS exome AF: 0.137

Gnomad4 FIN exome AF: 0.0588

Gnomad4 NFE exome AF: 0.0600

Gnomad4 OTH exome AF: 0.0866

GnomAD4 genome AF: 0.0893 AC: 13587 AN: 152234 Hom.: 676 Cov.: 32 AF XY: 0.0908 AC XY: 6760 AN XY: 74446

Gnomad4 AFR AF: 0.130

Gnomad4 AMR AF: 0.0797

Gnomad4 ASJ AF: 0.172

Gnomad4 EAS AF: 0.110

Gnomad4 SAS AF: 0.142

Gnomad4 FIN AF: 0.0569

Gnomad4 NFE AF: 0.0628

Gnomad4 OTH AF: 0.0953

Alfa AF: 0.0814 Hom.: 299

Bravo AF: 0.0910

TwinsUK AF: 0.0572 AC: 212

ALSPAC AF: 0.0633 AC: 244

ESP6500AA AF: 0.115 AC: 508

ESP6500EA AF: 0.0584 AC: 502

ExAC AF: 0.0873 AC: 10605

Asia WGS AF: 0.114 AC: 398 AN: 3478

EpiCase AF: 0.0698

EpiControl AF: 0.0751

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 29, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 02, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 03, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.061	.;T;T;T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.44	T;T;T;T;T
MetaRNN	Benign	0.0013	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;N;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.1	D;.;D;D;D
REVEL	Benign	0.052
Sift	Benign	0.20	T;.;D;T;T
Sift4G	Benign	0.16	T;T;T;T;T
Polyphen		0.0010	B;.;B;.;.
Vest4		0.19
MutPred		0.36		Gain of disorder (P = 0.003);.;Gain of disorder (P = 0.003);.;.;
MPC		0.074
ClinPred		0.032	T
GERP RS		5.9
Varity_R		0.47
gMVP		0.41

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: rs2792205; hg19: chr14-64560091; COSMIC: COSV59962991; COSMIC: COSV59962991;