14-64030045-T-C

Position:

• chr14-64030045-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_182914.3(SYNE2):​c.6865T>C​(p.Leu2289Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0489 in 1,613,850 control chromosomes in the GnomAD database, including 2,616 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.079 (649 hom., cov: 33)
  • Exomes 𝑓: 0.046 (1967 hom.)
• Consequence: SYNE2 NM_182914.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.00

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 14-64030045-T-C is Benign according to our data. Variant chr14-64030045-T-C is described in ClinVar as [Benign]. Clinvar id is 130505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64030045-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.6865T>C	p.Leu2289Leu	synonymous_variant	44/116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.6865T>C	p.Leu2289Leu	synonymous_variant	44/116	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.0793 AC: 12047 AN: 151974 Hom.: 643 Cov.: 33

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0922

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.0519

Gnomad SAS AF: 0.0382

Gnomad FIN AF: 0.0620

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0436

Gnomad OTH AF: 0.0767

GnomAD3 exomes AF: 0.0584 AC: 14564 AN: 249388 Hom.: 580 AF XY: 0.0539 AC XY: 7297 AN XY: 135314

Gnomad AFR exome AF: 0.149

Gnomad AMR exome AF: 0.103

Gnomad ASJ exome AF: 0.0483

Gnomad EAS exome AF: 0.0526

Gnomad SAS exome AF: 0.0412

Gnomad FIN exome AF: 0.0524

Gnomad NFE exome AF: 0.0402

Gnomad OTH exome AF: 0.0518

GnomAD4 exome AF: 0.0457 AC: 66861 AN: 1461758 Hom.: 1967 Cov.: 36 AF XY: 0.0452 AC XY: 32846 AN XY: 727166

Gnomad4 AFR exome AF: 0.152

Gnomad4 AMR exome AF: 0.103

Gnomad4 ASJ exome AF: 0.0458

Gnomad4 EAS exome AF: 0.0567

Gnomad4 SAS exome AF: 0.0391

Gnomad4 FIN exome AF: 0.0510

Gnomad4 NFE exome AF: 0.0399

Gnomad4 OTH exome AF: 0.0501

GnomAD4 genome AF: 0.0794 AC: 12072 AN: 152092 Hom.: 649 Cov.: 33 AF XY: 0.0790 AC XY: 5876 AN XY: 74350

Gnomad4 AFR AF: 0.149

Gnomad4 AMR AF: 0.0921

Gnomad4 ASJ AF: 0.0493

Gnomad4 EAS AF: 0.0521

Gnomad4 SAS AF: 0.0382

Gnomad4 FIN AF: 0.0620

Gnomad4 NFE AF: 0.0436

Gnomad4 OTH AF: 0.0773

Alfa AF: 0.0556 Hom.: 213

Bravo AF: 0.0837

Asia WGS AF: 0.0550 AC: 191 AN: 3476

EpiCase AF: 0.0382

EpiControl AF: 0.0398

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Benign:2

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 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 15, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.9
DANN	Benign	0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs11850509; hg19: chr14-64496763;