rs8010699

Variant names:

• chr14-64056125-A-G
• rs8010699
• NM_182914.3:c.9926A>G

Your query was ambiguous. Multiple possible variants found:

• chr14-64056125-A-G
• chr14-64056125-A-T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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:6
• Conservation: PhyloP100: 1.13
• Publications: 43 publications found

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]

SYNE2 Gene-Disease associations (from GenCC):

• autosomal dominant Emery-Dreifuss muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Emery-Dreifuss muscular dystrophy 5, autosomal dominant

  Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics
• left ventricular noncompaction

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 130521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.9926A>G	p.His3309Arg	missense_variant	Exon 49 of 116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.9926A>G	p.His3309Arg	missense_variant	Exon 49 of 116	1	NM_182914.3	ENSP00000450831.2

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

GnomAD2 exomes AF: 0.812 AC: 202701 AN: 249528 AF XY: 0.819

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 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

African (AFR) AF: 0.428 AC: 14317 AN: 33478

American (AMR) AF: 0.816 AC: 36486 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.742 AC: 19399 AN: 26134

East Asian (EAS) AF: 0.777 AC: 30857 AN: 39696

South Asian (SAS) AF: 0.796 AC: 68638 AN: 86254

European-Finnish (FIN) AF: 0.867 AC: 46327 AN: 53420

Middle Eastern (MID) AF: 0.807 AC: 4655 AN: 5766

European-Non Finnish (NFE) AF: 0.876 AC: 974264 AN: 1111896

Other (OTH) AF: 0.821 AC: 49545 AN: 60382

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

African (AFR) AF: 0.452 AC: 18738 AN: 41434

American (AMR) AF: 0.780 AC: 11916 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.754 AC: 2612 AN: 3466

East Asian (EAS) AF: 0.793 AC: 4100 AN: 5172

South Asian (SAS) AF: 0.783 AC: 3774 AN: 4818

European-Finnish (FIN) AF: 0.856 AC: 9051 AN: 10574

Middle Eastern (MID) AF: 0.752 AC: 221 AN: 294

European-Non Finnish (NFE) AF: 0.869 AC: 59111 AN: 68008

Other (OTH) AF: 0.755 AC: 1593 AN: 2110

Alfa AF: 0.829 Hom.: 251328

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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
DEOGEN2	Benign	0.019	.;T;T;T
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;.
PhyloP100		1.1
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
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs8010699; hg19: chr14-64522843; COSMIC: COSV107422170;