rs4027404

Variant names:

• chr14-64031212-G-A
• rs4027404
• NM_182914.3:c.7076G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-64031212-G-A
• chr14-64031212-G-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.7076G>A​(p.Ser2359Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.854 in 1,613,954 control chromosomes in the GnomAD database, including 595,786 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. S2359G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.76 (46033 hom., cov: 33)
  • Exomes 𝑓: 0.86 (549753 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.999
• Publications: 38 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=8.300542E-7).
• BP6: Variant 14-64031212-G-A is Benign according to our data. Variant chr14-64031212-G-A is described in ClinVar as Benign. ClinVar VariationId is 130508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.876 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.7076G>A	p.Ser2359Asn	missense_variant	Exon 45 of 116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.7076G>A	p.Ser2359Asn	missense_variant	Exon 45 of 116	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.762 AC: 115800 AN: 152060 Hom.: 46025 Cov.: 33

Gnomad AFR AF: 0.511

Gnomad AMI AF: 0.884

Gnomad AMR AF: 0.800

Gnomad ASJ AF: 0.796

Gnomad EAS AF: 0.790

Gnomad SAS AF: 0.785

Gnomad FIN AF: 0.864

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.882

Gnomad OTH AF: 0.776

GnomAD2 exomes AF: 0.825 AC: 205865 AN: 249398 AF XY: 0.831

Gnomad AFR exome AF: 0.498

Gnomad AMR exome AF: 0.832

Gnomad ASJ exome AF: 0.781

Gnomad EAS exome AF: 0.781

Gnomad FIN exome AF: 0.872

Gnomad NFE exome AF: 0.879

Gnomad OTH exome AF: 0.825

GnomAD4 exome AF: 0.864 AC: 1263123 AN: 1461776 Hom.: 549753 Cov.: 59 AF XY: 0.863 AC XY: 627386 AN XY: 727188

African (AFR) AF: 0.483 AC: 16155 AN: 33470

American (AMR) AF: 0.827 AC: 37001 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.783 AC: 20461 AN: 26132

East Asian (EAS) AF: 0.774 AC: 30705 AN: 39692

South Asian (SAS) AF: 0.797 AC: 68751 AN: 86254

European-Finnish (FIN) AF: 0.876 AC: 46780 AN: 53410

Middle Eastern (MID) AF: 0.800 AC: 4615 AN: 5768

European-Non Finnish (NFE) AF: 0.889 AC: 988261 AN: 1111936

Other (OTH) AF: 0.834 AC: 50394 AN: 60392

GnomAD4 genome AF: 0.761 AC: 115842 AN: 152178 Hom.: 46033 Cov.: 33 AF XY: 0.761 AC XY: 56633 AN XY: 74390

African (AFR) AF: 0.510 AC: 21165 AN: 41474

American (AMR) AF: 0.800 AC: 12223 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.796 AC: 2761 AN: 3470

East Asian (EAS) AF: 0.790 AC: 4088 AN: 5174

South Asian (SAS) AF: 0.786 AC: 3794 AN: 4830

European-Finnish (FIN) AF: 0.864 AC: 9168 AN: 10606

Middle Eastern (MID) AF: 0.745 AC: 219 AN: 294

European-Non Finnish (NFE) AF: 0.882 AC: 59984 AN: 68028

Other (OTH) AF: 0.774 AC: 1634 AN: 2112

Alfa AF: 0.838 Hom.: 145690

Bravo AF: 0.746

TwinsUK AF: 0.887 AC: 3289

ALSPAC AF: 0.879 AC: 3389

ESP6500AA AF: 0.528 AC: 1968

ESP6500EA AF: 0.878 AC: 7224

ExAC AF: 0.821 AC: 99123

Asia WGS AF: 0.764 AC: 2656 AN: 3478

EpiCase AF: 0.878

EpiControl AF: 0.872

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

Jan 13, 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. -

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

- -

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	0.074
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	15
DANN	Benign	0.47
DEOGEN2	Benign	0.014	.;T;T;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.74	T;T;T;T
MetaRNN	Benign	8.3e-7	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L;.;L;.
PhyloP100		1.0
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.48	N;.;N;N
REVEL	Benign	0.090
Sift	Benign	0.34	T;.;T;T
Sift4G	Benign	0.32	T;T;T;T
Polyphen		0.0040	B;.;B;.
Vest4		0.033
MPC		0.049
ClinPred		0.00080	T
GERP RS		3.1
Varity_R		0.030
gMVP		0.15
Mutation Taster		=294/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4027404; hg19: chr14-64497930; COSMIC: COSV107421831;