rs149227847

chr14-64167345-G-Achr14-64167345-G-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.16718G>A(p.Arg5573Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000983 in 1,614,170 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5573W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00088 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00099 (1 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 7.54

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=0.029416144).
• BP6: Variant 14-64167345-G-A is Benign according to our data. Variant chr14-64167345-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 199220.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=3, Uncertain_significance=1}. Variant chr14-64167345-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00088 (134/152304) while in subpopulation AMR AF= 0.00379 (58/15296). AF 95% confidence interval is 0.00301. There are 0 homozygotes in gnomad4. There are 70 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 134 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.16718G>A	p.Arg5573Gln	missense_variant	91/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.16718G>A	p.Arg5573Gln	missense_variant	91/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.000881 AC: 134 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000819 AC: 206 AN: 251384 Hom.: 0 AF XY: 0.000817 AC XY: 111 AN XY: 135866

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000994 AC: 1453 AN: 1461866 Hom.: 1 Cov.: 30 AF XY: 0.000958 AC XY: 697 AN XY: 727236

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00172

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00117

Gnomad4 OTH exome AF: 0.000927

GnomAD4 genome AF: 0.000880 AC: 134 AN: 152304 Hom.: 0 Cov.: 33 AF XY: 0.000940 AC XY: 70 AN XY: 74478

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000926

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000943 Hom.: 1

Bravo AF: 0.00103

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000774 AC: 94

EpiCase AF: 0.000545

EpiControl AF: 0.00166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	SYNE2: BP4, BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 27, 2015	- -

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

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2023	- -
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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 29, 2022

Variant summary: SYNE2 c.16718G>A (p.Arg5573Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00082 in 251384 control chromosomes, predominantly at a frequency of 0.0019 within the Latino subpopulation in the gnomAD database, suggesting that it is a benign polymorphism found primarily in individuals of Latino ancestry. To our knowledge, no occurrence of c.16718G>A in individuals affected with Autosomal Dominant Emery-Dreifuss Muscular Dystrophy 5 and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as benign, one as likely benign, and one classified it as VUS. Based on the evidence outlined above, the variant was classified as likely benign. -

SYNE2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 01, 2022

This variant is classified as likely 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	-0.055	T
BayesDel_noAF	Pathogenic	0.14
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.029	T;T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Pathogenic	3.2	M;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.6	D;.;D;D;D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D;.;D;D;D
Sift4G	Uncertain	0.023	D;D;D;D;D
Polyphen		1.0	D;.;D;D;.
Vest4		0.52
MVP		0.47
MPC		0.34
ClinPred		0.13	T
GERP RS		5.8
Varity_R		0.40
gMVP		0.25

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: rs149227847; hg19: chr14-64634063; COSMIC: COSV105905903; COSMIC: COSV105905903;