rs8010699

chr14-64056125-A-Gchr14-64056125-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.9926A>G(p.His3309Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.841 in 1,613,806 control chromosomes in the GnomAD database, including 577,937 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H3309L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.74 (43673 hom., cov: 30)
  • Exomes 𝑓: 0.85 (534264 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.13

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=8.994511E-7).
• BP6: Variant 14-64056125-A-G is Benign according to our data. Variant chr14-64056125-A-G is described in ClinVar as [Benign]. Clinvar id is 130521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64056125-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.863 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.9926A>G	p.His3309Arg	missense_variant	49/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.9926A>G	p.His3309Arg	missense_variant	49/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.736 AC: 111885 AN: 151938 Hom.: 43662 Cov.: 30

Gnomad AFR AF: 0.452

Gnomad AMI AF: 0.890

Gnomad AMR AF: 0.780

Gnomad ASJ AF: 0.754

Gnomad EAS AF: 0.793

Gnomad SAS AF: 0.782

Gnomad FIN AF: 0.856

Gnomad MID AF: 0.753

Gnomad NFE AF: 0.869

Gnomad OTH AF: 0.759

GnomAD3 exomes AF: 0.812 AC: 202701 AN: 249528 Hom.: 83783 AF XY: 0.819 AC XY: 110831 AN XY: 135390

Gnomad AFR exome AF: 0.442

Gnomad AMR exome AF: 0.821

Gnomad ASJ exome AF: 0.742

Gnomad EAS exome AF: 0.786

Gnomad SAS exome AF: 0.790

Gnomad FIN exome AF: 0.864

Gnomad NFE exome AF: 0.867

Gnomad OTH exome AF: 0.810

GnomAD4 exome AF: 0.851 AC: 1244488 AN: 1461750 Hom.: 534264 Cov.: 54 AF XY: 0.851 AC XY: 618479 AN XY: 727188

Gnomad4 AFR exome AF: 0.428

Gnomad4 AMR exome AF: 0.816

Gnomad4 ASJ exome AF: 0.742

Gnomad4 EAS exome AF: 0.777

Gnomad4 SAS exome AF: 0.796

Gnomad4 FIN exome AF: 0.867

Gnomad4 NFE exome AF: 0.876

Gnomad4 OTH exome AF: 0.821

GnomAD4 genome AF: 0.736 AC: 111928 AN: 152056 Hom.: 43673 Cov.: 30 AF XY: 0.737 AC XY: 54793 AN XY: 74330

Gnomad4 AFR AF: 0.452

Gnomad4 AMR AF: 0.780

Gnomad4 ASJ AF: 0.754

Gnomad4 EAS AF: 0.793

Gnomad4 SAS AF: 0.783

Gnomad4 FIN AF: 0.856

Gnomad4 NFE AF: 0.869

Gnomad4 OTH AF: 0.755

Alfa AF: 0.843 Hom.: 130678

Bravo AF: 0.719

TwinsUK AF: 0.879 AC: 3259

ALSPAC AF: 0.869 AC: 3351

ESP6500AA AF: 0.479 AC: 1855

ESP6500EA AF: 0.864 AC: 7140

ExAC AF: 0.807 AC: 97511

Asia WGS AF: 0.758 AC: 2637 AN: 3478

EpiCase AF: 0.868

EpiControl AF: 0.861

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:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 15, 2013

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	2.4
Dann	Benign	0.54
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.74	T;T;T;T
MetaRNN	Benign	9.0e-7	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;N;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.5	N;.;N;N
REVEL	Benign	0.026
Sift	Benign	0.038	D;.;D;T
Sift4G	Uncertain	0.011	D;D;D;D
Polyphen		0.039	B;.;B;.
Vest4		0.065
MPC		0.060
ClinPred		0.011	T
GERP RS		3.4
Varity_R		0.051
gMVP		0.063

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: rs8010699; hg19: chr14-64522843;