rs45590135

Positions:

• chr14-64031299-A-G

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.7163A>G​(p.Glu2388Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,614,190 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. E2388K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0019 (9 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.0260

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042034388).
• BP6: Variant 14-64031299-A-G is Benign according to our data. Variant chr14-64031299-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 252805.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1, Benign=3}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00122 (186/152368) while in subpopulation NFE AF= 0.002 (136/68038). AF 95% confidence interval is 0.00173. There are 1 homozygotes in gnomad4. There are 79 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 186 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.7163A>G	p.Glu2388Gly	missense_variant	45/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.7163A>G	p.Glu2388Gly	missense_variant	45/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 186 AN: 152250 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00200

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00168 AC: 419 AN: 248780 Hom.: 1 AF XY: 0.00184 AC XY: 248 AN XY: 135080

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00249

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00245

Gnomad FIN exome AF: 0.000464

Gnomad NFE exome AF: 0.00212

Gnomad OTH exome AF: 0.00347

GnomAD4 exome AF: 0.00187 AC: 2732 AN: 1461822 Hom.: 9 Cov.: 64 AF XY: 0.00192 AC XY: 1394 AN XY: 727204

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00148

Gnomad4 ASJ exome AF: 0.00245

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00232

Gnomad4 FIN exome AF: 0.000618

Gnomad4 NFE exome AF: 0.00199

Gnomad4 OTH exome AF: 0.00180

GnomAD4 genome AF: 0.00122 AC: 186 AN: 152368 Hom.: 1 Cov.: 34 AF XY: 0.00106 AC XY: 79 AN XY: 74510

Gnomad4 AFR AF: 0.000264

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00200

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00169 Hom.: 1

Bravo AF: 0.00114

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00170 AC: 14

ExAC AF: 0.00155 AC: 187

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00180

EpiControl AF: 0.00225

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 16, 2021	The c.7163A>G (p.E2388G) alteration is located in exon 45 (coding exon 44) of the SYNE2 gene. This alteration results from a A to G substitution at nucleotide position 7163, causing the glutamic acid (E) at amino acid position 2388 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 18, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 13, 2015	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 06, 2020	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	SYNE2: BS1, BS2 -

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 04, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	13
DANN	Benign	0.88
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.64	T;T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.0042	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.;L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Uncertain	-2.6	D;.;D;N
REVEL	Benign	0.051
Sift	Benign	0.12	T;.;T;T
Sift4G	Benign	0.36	T;T;T;T
Polyphen		0.0040	B;.;B;.
Vest4		0.060
MVP		0.24
MPC		0.054
ClinPred		0.0057	T
GERP RS		1.0
Varity_R		0.048
gMVP		0.15

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: rs45590135; hg19: chr14-64498017;