rs7157465

chr14-64031211-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.7075A>G(p.Ser2359Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00876 in 1,614,154 control chromosomes in the GnomAD database, including 752 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. S2359N) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.037 (327 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (425 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.68

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016507208).
• BP6: Variant 14-64031211-A-G is Benign according to our data. Variant chr14-64031211-A-G is described in ClinVar as [Benign]. Clinvar id is 130507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64031211-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.7075A>G	p.Ser2359Gly	missense_variant	45/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.7075A>G	p.Ser2359Gly	missense_variant	45/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.0365 AC: 5557 AN: 152188 Hom.: 324 Cov.: 33

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0148

Gnomad SAS AF: 0.0157

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0263

GnomAD3 exomes AF: 0.0116 AC: 2895 AN: 249390 Hom.: 126 AF XY: 0.00981 AC XY: 1328 AN XY: 135312

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.00730

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00884

Gnomad SAS exome AF: 0.0130

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000283

Gnomad OTH exome AF: 0.00528

GnomAD4 exome AF: 0.00586 AC: 8563 AN: 1461848 Hom.: 425 Cov.: 31 AF XY: 0.00561 AC XY: 4083 AN XY: 727224

Gnomad4 AFR exome AF: 0.136

Gnomad4 AMR exome AF: 0.00751

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0372

Gnomad4 SAS exome AF: 0.0139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000285

Gnomad4 OTH exome AF: 0.0107

GnomAD4 genome AF: 0.0366 AC: 5579 AN: 152306 Hom.: 327 Cov.: 33 AF XY: 0.0354 AC XY: 2638 AN XY: 74484

Gnomad4 AFR AF: 0.123

Gnomad4 AMR AF: 0.0144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0148

Gnomad4 SAS AF: 0.0155

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.0293

Alfa AF: 0.00817 Hom.: 72

Bravo AF: 0.0414

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.120 AC: 446

ESP6500EA AF: 0.000608 AC: 5

ExAC AF: 0.0144 AC: 1736

Asia WGS AF: 0.0320 AC: 110 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:8

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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 22, 2020	- -

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

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Apr 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
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 provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

SYNE2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2020

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	16
Dann	Benign	0.96
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.83	T;T;T;T
MetaRNN	Benign	0.0017	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;.;M;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.6	N;.;N;N
REVEL	Benign	0.081
Sift	Benign	0.037	D;.;D;D
Sift4G	Uncertain	0.040	D;D;D;D
Polyphen		0.0040	B;.;B;.
Vest4		0.085
MPC		0.047
ClinPred		0.013	T
GERP RS		2.7
Varity_R		0.055
gMVP		0.11

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: rs7157465; hg19: chr14-64497929; COSMIC: COSV59952619;