rs11628107

chr14-64051603-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.7690A>G(p.Ile2564Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0286 in 1,613,676 control chromosomes in the GnomAD database, including 893 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (99 hom., cov: 32)
  • Exomes 𝑓: 0.029 (794 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0980

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=0.002633661).
• BP6: Variant 14-64051603-A-G is Benign according to our data. Variant chr14-64051603-A-G is described in ClinVar as [Benign]. Clinvar id is 130512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64051603-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0613 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.7690A>G	p.Ile2564Val	missense_variant	48/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.7690A>G	p.Ile2564Val	missense_variant	48/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.0293 AC: 4460 AN: 152202 Hom.: 99 Cov.: 32

Gnomad AFR AF: 0.00765

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0646

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.0496

Gnomad SAS AF: 0.00994

Gnomad FIN AF: 0.0603

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0309

Gnomad OTH AF: 0.0263

GnomAD3 exomes AF: 0.0359 AC: 8930 AN: 248864 Hom.: 264 AF XY: 0.0328 AC XY: 4435 AN XY: 135120

Gnomad AFR exome AF: 0.00777

Gnomad AMR exome AF: 0.0853

Gnomad ASJ exome AF: 0.0140

Gnomad EAS exome AF: 0.0491

Gnomad SAS exome AF: 0.0126

Gnomad FIN exome AF: 0.0519

Gnomad NFE exome AF: 0.0281

Gnomad OTH exome AF: 0.0298

GnomAD4 exome AF: 0.0285 AC: 41664 AN: 1461356 Hom.: 794 Cov.: 30 AF XY: 0.0279 AC XY: 20270 AN XY: 727018

Gnomad4 AFR exome AF: 0.00695

Gnomad4 AMR exome AF: 0.0833

Gnomad4 ASJ exome AF: 0.0133

Gnomad4 EAS exome AF: 0.0526

Gnomad4 SAS exome AF: 0.0110

Gnomad4 FIN exome AF: 0.0503

Gnomad4 NFE exome AF: 0.0270

Gnomad4 OTH exome AF: 0.0259

GnomAD4 genome AF: 0.0293 AC: 4459 AN: 152320 Hom.: 99 Cov.: 32 AF XY: 0.0307 AC XY: 2288 AN XY: 74474

Gnomad4 AFR AF: 0.00762

Gnomad4 AMR AF: 0.0646

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.0495

Gnomad4 SAS AF: 0.00995

Gnomad4 FIN AF: 0.0603

Gnomad4 NFE AF: 0.0309

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.0287 Hom.: 174

Bravo AF: 0.0283

TwinsUK AF: 0.0275 AC: 102

ALSPAC AF: 0.0259 AC: 100

ESP6500AA AF: 0.0112 AC: 40

ESP6500EA AF: 0.0280 AC: 228

ExAC AF: 0.0328 AC: 3968

Asia WGS AF: 0.0300 AC: 103 AN: 3478

EpiCase AF: 0.0226

EpiControl AF: 0.0239

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	0.79
Dann	Benign	0.41
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.71	T;T;T;T
MetaRNN	Benign	0.0026	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;N;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.24	N;.;N;N
REVEL	Benign	0.067
Sift	Benign	1.0	T;.;T;T
Sift4G	Benign	0.29	T;T;T;T
Polyphen		0.012	B;.;B;.
Vest4		0.11
MPC		0.045
ClinPred		0.0018	T
GERP RS		4.0
Varity_R		0.017
gMVP		0.018

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: rs11628107; hg19: chr14-64518321;