rs17101661

chr14-64097962-G-A

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.12122G>A(p.Arg4041His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,614,186 control chromosomes in the GnomAD database, including 211 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4041C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.017 (35 hom., cov: 32)
  • Exomes 𝑓: 0.014 (176 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.98

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=0.0019463599).
• BP6: Variant 14-64097962-G-A is Benign according to our data. Variant chr14-64097962-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 130465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64097962-G-A is described in Lovd as [Benign]. Variant chr14-64097962-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0175 (2661/152324) while in subpopulation AFR AF= 0.0281 (1167/41568). AF 95% confidence interval is 0.0267. There are 35 homozygotes in gnomad4. There are 1250 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 2660 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.12122G>A	p.Arg4041His	missense_variant	62/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.12122G>A	p.Arg4041His	missense_variant	62/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2660 AN: 152206 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.0340

Gnomad AMR AF: 0.0151

Gnomad ASJ AF: 0.0401

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0145

Gnomad OTH AF: 0.0253

GnomAD3 exomes AF: 0.0124 AC: 3113 AN: 251440 Hom.: 33 AF XY: 0.0121 AC XY: 1640 AN XY: 135892

Gnomad AFR exome AF: 0.0260

Gnomad AMR exome AF: 0.0128

Gnomad ASJ exome AF: 0.0386

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00229

Gnomad FIN exome AF: 0.00152

Gnomad NFE exome AF: 0.0143

Gnomad OTH exome AF: 0.0205

GnomAD4 exome AF: 0.0140 AC: 20456 AN: 1461862 Hom.: 176 Cov.: 31 AF XY: 0.0137 AC XY: 9978 AN XY: 727238

Gnomad4 AFR exome AF: 0.0284

Gnomad4 AMR exome AF: 0.0141

Gnomad4 ASJ exome AF: 0.0370

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00235

Gnomad4 FIN exome AF: 0.00154

Gnomad4 NFE exome AF: 0.0149

Gnomad4 OTH exome AF: 0.0156

GnomAD4 genome AF: 0.0175 AC: 2661 AN: 152324 Hom.: 35 Cov.: 32 AF XY: 0.0168 AC XY: 1250 AN XY: 74488

Gnomad4 AFR AF: 0.0281

Gnomad4 AMR AF: 0.0151

Gnomad4 ASJ AF: 0.0401

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.0145

Gnomad4 OTH AF: 0.0251

Alfa AF: 0.0164 Hom.: 54

Bravo AF: 0.0197

TwinsUK AF: 0.0189 AC: 70

ALSPAC AF: 0.0200 AC: 77

ESP6500AA AF: 0.0238 AC: 105

ESP6500EA AF: 0.0162 AC: 139

ExAC AF: 0.0120 AC: 1461

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0163

EpiControl AF: 0.0164

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not specified Benign:2

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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 12, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	0.20
Dann	Benign	0.88
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0089	N
LIST_S2	Benign	0.59	T;T;T;T;T
MetaRNN	Benign	0.0019	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	N;.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.69	N;.;N;N;N
REVEL	Benign	0.042
Sift	Benign	0.17	T;.;T;T;T
Sift4G	Benign	0.13	T;T;T;T;T
Polyphen		0.17	B;.;B;.;.
Vest4		0.053
MPC		0.084
ClinPred		0.00056	T
GERP RS		-6.1
Varity_R		0.013
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17101661; hg19: chr14-64564680;