rs7146588

Positions:

• chr14-64009962-T-A
• chr14-64009962-T-G

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.4578-4T>A variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0003185
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.335

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 (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 id is 130499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64009962-T-A is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.4578-4T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.4578-4T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_182914.3	ENSP00000450831	P4

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

GnomAD3 exomes AF: 0.241 AC: 59843 AN: 248812 Hom.: 8676 AF XY: 0.230 AC XY: 31076 AN XY: 135006

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 SAS exome AF: 0.225

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

Gnomad4 AFR exome AF: 0.609

Gnomad4 AMR exome AF: 0.329

Gnomad4 ASJ exome AF: 0.254

Gnomad4 EAS exome AF: 0.270

Gnomad4 SAS exome AF: 0.219

Gnomad4 FIN exome AF: 0.178

Gnomad4 NFE exome AF: 0.178

Gnomad4 OTH exome AF: 0.219

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

Gnomad4 AFR AF: 0.583

Gnomad4 AMR AF: 0.303

Gnomad4 ASJ AF: 0.247

Gnomad4 EAS AF: 0.227

Gnomad4 SAS AF: 0.238

Gnomad4 FIN AF: 0.179

Gnomad4 NFE AF: 0.185

Gnomad4 OTH AF: 0.280

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

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.8
DANN	Benign	0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs7146588; hg19: chr14-64476680; COSMIC: COSV59952600;