rs34843668

chr14-64052991-A-T

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.9078A>T(p.Glu3026Asp) 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 1,610,852 control chromosomes in the GnomAD database, including 889 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 (101 hom., cov: 33)
  • Exomes 𝑓: 0.029 (788 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.965

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=0.002384305).
• BP6: Variant 14-64052991-A-T is Benign according to our data. Variant chr14-64052991-A-T is described in ClinVar as [Benign]. Clinvar id is 130518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64052991-A-T is described in Lovd as [Benign]. Variant chr14-64052991-A-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.9078A>T	p.Glu3026Asp	missense_variant	48/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.9078A>T	p.Glu3026Asp	missense_variant	48/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.0294 AC: 4467 AN: 152186 Hom.: 101 Cov.: 33

Gnomad AFR AF: 0.00765

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0649

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.0494

Gnomad SAS AF: 0.0102

Gnomad FIN AF: 0.0609

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0309

Gnomad OTH AF: 0.0263

GnomAD3 exomes AF: 0.0360 AC: 8829 AN: 245360 Hom.: 257 AF XY: 0.0330 AC XY: 4388 AN XY: 133136

Gnomad AFR exome AF: 0.00774

Gnomad AMR exome AF: 0.0858

Gnomad ASJ exome AF: 0.0142

Gnomad EAS exome AF: 0.0488

Gnomad SAS exome AF: 0.0126

Gnomad FIN exome AF: 0.0520

Gnomad NFE exome AF: 0.0280

Gnomad OTH exome AF: 0.0302

GnomAD4 exome AF: 0.0285 AC: 41577 AN: 1458548 Hom.: 788 Cov.: 37 AF XY: 0.0279 AC XY: 20214 AN XY: 725274

Gnomad4 AFR exome AF: 0.00690

Gnomad4 AMR exome AF: 0.0834

Gnomad4 ASJ exome AF: 0.0134

Gnomad4 EAS exome AF: 0.0524

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: 4466 AN: 152304 Hom.: 101 Cov.: 33 AF XY: 0.0308 AC XY: 2297 AN XY: 74478

Gnomad4 AFR AF: 0.00762

Gnomad4 AMR AF: 0.0648

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.0494

Gnomad4 SAS AF: 0.0102

Gnomad4 FIN AF: 0.0609

Gnomad4 NFE AF: 0.0308

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.0283 Hom.: 53

Bravo AF: 0.0283

TwinsUK AF: 0.0270 AC: 100

ALSPAC AF: 0.0259 AC: 100

ESP6500AA AF: 0.0114 AC: 41

ESP6500EA AF: 0.0257 AC: 209

ExAC AF: 0.0327 AC: 3951

Asia WGS AF: 0.0300 AC: 104 AN: 3476

EpiCase AF: 0.0226

EpiControl AF: 0.0238

ClinVar

Significance: 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	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not specified Benign:2

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	-	- -

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	0.22
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	14
Dann	Benign	0.95
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.83	T;T;T;T
MetaRNN	Benign	0.0024	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;.;L;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.7	N;.;N;N
REVEL	Benign	0.059
Sift	Benign	0.030	D;.;D;D
Sift4G	Benign	0.082	T;D;T;D
Polyphen		0.63	P;.;P;.
Vest4		0.15
MutPred		0.094		Loss of ubiquitination at K3027 (P = 0.0642);.;Loss of ubiquitination at K3027 (P = 0.0642);.;
MPC		0.18
ClinPred		0.021	T
GERP RS		-0.54
Varity_R		0.087
gMVP		0.075

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: rs34843668; hg19: chr14-64519709;