NM_182914.3:c.4578-4T>A

Variant names:

• chr14-64009962-T-A
• rs7146588
• NM_182914.3:c.4578-4T>A

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.4578-4T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 1,611,048 control chromosomes in the GnomAD database, including 43,218 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (9574 hom., cov: 32)
  • Exomes 𝑓: 0.20 (33644 hom.)
• Consequence: SYNE2 NM_182914.3 splice_region, intron
• Scores: Splicing: ADA: 0.0003185
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.335
• Publications: 11 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 (BayesDel_noAF=-0.81).
• BP6: Variant 14-64009962-T-A is Benign according to our data. Variant chr14-64009962-T-A is described in ClinVar as Benign. ClinVar VariationId is 130499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.4578-4T>A		splice_region_variant, intron_variant	Intron 31 of 115	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.4578-4T>A		splice_region_variant, intron_variant	Intron 31 of 115	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.310 AC: 47088 AN: 151992 Hom.: 9540 Cov.: 32

Gnomad AFR AF: 0.582

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.304

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.227

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.279

GnomAD2 exomes AF: 0.241 AC: 59843 AN: 248812 AF XY: 0.230

Gnomad AFR exome AF: 0.596

Gnomad AMR exome AF: 0.331

Gnomad ASJ exome AF: 0.254

Gnomad EAS exome AF: 0.221

Gnomad FIN exome AF: 0.177

Gnomad NFE exome AF: 0.183

Gnomad OTH exome AF: 0.233

GnomAD4 exome AF: 0.200 AC: 292388 AN: 1458938 Hom.: 33644 Cov.: 31 AF XY: 0.200 AC XY: 144891 AN XY: 725898

African (AFR) AF: 0.609 AC: 20319 AN: 33350

American (AMR) AF: 0.329 AC: 14700 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 6619 AN: 26106

East Asian (EAS) AF: 0.270 AC: 10700 AN: 39660

South Asian (SAS) AF: 0.219 AC: 18869 AN: 86138

European-Finnish (FIN) AF: 0.178 AC: 9487 AN: 53396

Middle Eastern (MID) AF: 0.198 AC: 1068 AN: 5394

European-Non Finnish (NFE) AF: 0.178 AC: 197405 AN: 1109964

Other (OTH) AF: 0.219 AC: 13221 AN: 60238

GnomAD4 genome AF: 0.310 AC: 47173 AN: 152110 Hom.: 9574 Cov.: 32 AF XY: 0.309 AC XY: 22953 AN XY: 74356

African (AFR) AF: 0.583 AC: 24161 AN: 41460

American (AMR) AF: 0.303 AC: 4639 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 856 AN: 3472

East Asian (EAS) AF: 0.227 AC: 1178 AN: 5184

South Asian (SAS) AF: 0.238 AC: 1150 AN: 4822

European-Finnish (FIN) AF: 0.179 AC: 1890 AN: 10572

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.185 AC: 12595 AN: 67990

Other (OTH) AF: 0.280 AC: 591 AN: 2114

Alfa AF: 0.226 Hom.: 1516

Bravo AF: 0.331

Asia WGS AF: 0.265 AC: 919 AN: 3478

EpiCase AF: 0.188

EpiControl AF: 0.188

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

not specified Benign:2

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.8
DANN	Benign	0.62
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00032
dbscSNV1_RF	Benign	0.0
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: rs7146588; hg19: chr14-64476680; COSMIC: COSV59952600;