rs35920722

chr14-64065488-C-Gchr14-64065488-C-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.10269C>G(p.Ile3423Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,614,010 control chromosomes in the GnomAD database, including 110 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. I3423F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (61 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (49 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0660

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=0.0020640492).
• BP6: Variant 14-64065488-C-G is Benign according to our data. Variant chr14-64065488-C-G is described in ClinVar as [Benign]. Clinvar id is 313552.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64065488-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.05 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.10269C>G	p.Ile3423Met	missense_variant	51/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.10269C>G	p.Ile3423Met	missense_variant	51/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.0151 AC: 2292 AN: 152032 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.0519

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00675

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.0168

GnomAD3 exomes AF: 0.00396 AC: 989 AN: 249530 Hom.: 28 AF XY: 0.00277 AC XY: 375 AN XY: 135382

Gnomad AFR exome AF: 0.0547

Gnomad AMR exome AF: 0.00354

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: 0.0000795

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00148 AC: 2168 AN: 1461860 Hom.: 49 Cov.: 32 AF XY: 0.00122 AC XY: 884 AN XY: 727234

Gnomad4 AFR exome AF: 0.0519

Gnomad4 AMR exome AF: 0.00360

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.00344

GnomAD4 genome AF: 0.0151 AC: 2299 AN: 152150 Hom.: 61 Cov.: 32 AF XY: 0.0140 AC XY: 1041 AN XY: 74386

Gnomad4 AFR AF: 0.0519

Gnomad4 AMR AF: 0.00674

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.00221 Hom.: 5

Bravo AF: 0.0174

ESP6500AA AF: 0.0492 AC: 187

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.00458 AC: 553

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 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 specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 04, 2017

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 14, 2018

- -

SYNE2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 05, 2019

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	0.091
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	9.5
Dann	Uncertain	0.98
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.82	T;T;T;T;T
MetaRNN	Benign	0.0021	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.46	N;.;N;N;N
REVEL	Benign	0.030
Sift	Benign	0.095	T;.;T;T;T
Sift4G	Uncertain	0.039	D;D;D;D;T
Polyphen		0.61	P;.;P;.;.
Vest4		0.25
MVP		0.45
MPC		0.12
ClinPred		0.00021	T
GERP RS		1.6
Varity_R		0.045
gMVP		0.051

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: rs35920722; hg19: chr14-64532206;