rs4027402

Variant names:

• chr14-64030031-C-T
• rs4027402
• NM_182914.3:c.6851C>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.6851C>T​(p.Ala2284Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.849 in 1,613,584 control chromosomes in the GnomAD database, including 591,320 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.73 (44065 hom., cov: 31)
  • Exomes 𝑓: 0.86 (547255 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.370
• Publications: 40 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=1.0792198E-6).
• BP6: Variant 14-64030031-C-T is Benign according to our data. Variant chr14-64030031-C-T is described in ClinVar as Benign. ClinVar VariationId is 130504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.875 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.6851C>T	p.Ala2284Val	missense_variant	Exon 44 of 116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.6851C>T	p.Ala2284Val	missense_variant	Exon 44 of 116	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.735 AC: 111657 AN: 151870 Hom.: 44065 Cov.: 31

Gnomad AFR AF: 0.419

Gnomad AMI AF: 0.886

Gnomad AMR AF: 0.789

Gnomad ASJ AF: 0.794

Gnomad EAS AF: 0.789

Gnomad SAS AF: 0.781

Gnomad FIN AF: 0.865

Gnomad MID AF: 0.745

Gnomad NFE AF: 0.881

Gnomad OTH AF: 0.756

GnomAD2 exomes AF: 0.818 AC: 203928 AN: 249272 AF XY: 0.825

Gnomad AFR exome AF: 0.401

Gnomad AMR exome AF: 0.827

Gnomad ASJ exome AF: 0.780

Gnomad EAS exome AF: 0.780

Gnomad FIN exome AF: 0.872

Gnomad NFE exome AF: 0.879

Gnomad OTH exome AF: 0.822

GnomAD4 exome AF: 0.861 AC: 1258443 AN: 1461594 Hom.: 547255 Cov.: 52 AF XY: 0.860 AC XY: 625284 AN XY: 727084

African (AFR) AF: 0.387 AC: 12942 AN: 33466

American (AMR) AF: 0.822 AC: 36744 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 20435 AN: 26132

East Asian (EAS) AF: 0.773 AC: 30685 AN: 39686

South Asian (SAS) AF: 0.794 AC: 68467 AN: 86236

European-Finnish (FIN) AF: 0.876 AC: 46775 AN: 53408

Middle Eastern (MID) AF: 0.794 AC: 4581 AN: 5766

European-Non Finnish (NFE) AF: 0.889 AC: 987863 AN: 1111802

Other (OTH) AF: 0.827 AC: 49951 AN: 60380

GnomAD4 genome AF: 0.735 AC: 111674 AN: 151990 Hom.: 44065 Cov.: 31 AF XY: 0.736 AC XY: 54668 AN XY: 74290

African (AFR) AF: 0.419 AC: 17318 AN: 41370

American (AMR) AF: 0.790 AC: 12056 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.794 AC: 2754 AN: 3468

East Asian (EAS) AF: 0.789 AC: 4083 AN: 5176

South Asian (SAS) AF: 0.782 AC: 3764 AN: 4814

European-Finnish (FIN) AF: 0.865 AC: 9144 AN: 10574

Middle Eastern (MID) AF: 0.741 AC: 218 AN: 294

European-Non Finnish (NFE) AF: 0.881 AC: 59941 AN: 68008

Other (OTH) AF: 0.754 AC: 1590 AN: 2108

Alfa AF: 0.819 Hom.: 153958

Bravo AF: 0.715

TwinsUK AF: 0.887 AC: 3290

ALSPAC AF: 0.880 AC: 3391

ESP6500AA AF: 0.436 AC: 1605

ESP6500EA AF: 0.878 AC: 7172

ExAC AF: 0.812 AC: 98062

Asia WGS AF: 0.753 AC: 2620 AN: 3478

EpiCase AF: 0.877

EpiControl AF: 0.871

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

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	0.11
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	8.0
DANN	Benign	0.72
DEOGEN2	Benign	0.032	.;T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.57	T;T;T;T
MetaRNN	Benign	0.0000011	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.;L;.
PhyloP100		0.37
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-2.0	N;.;N;N
REVEL	Benign	0.036
Sift	Benign	0.19	T;.;T;T
Sift4G	Benign	0.27	T;D;T;D
Polyphen		0.055	B;.;B;.
Vest4		0.079
MPC		0.049
ClinPred		0.0060	T
GERP RS		1.2
Varity_R		0.026
gMVP		0.16
Mutation Taster		=296/4	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: rs4027402; hg19: chr14-64496749; COSMIC: COSV107422304;