chr14-63942134-G-C

Position:

• chr14-63942134-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_182914.3(SYNE2):​c.399G>C​(p.Leu133Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0794 in 1,578,694 control chromosomes in the GnomAD database, including 6,239 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1276 hom., cov: 32)
  • Exomes 𝑓: 0.076 (4963 hom.)
• Consequence: SYNE2 NM_182914.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.888

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 14-63942134-G-C is Benign according to our data. Variant chr14-63942134-G-C is described in ClinVar as [Benign]. Clinvar id is 130496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-63942134-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.888 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.399G>C	p.Leu133Leu	synonymous_variant	6/116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.399G>C	p.Leu133Leu	synonymous_variant	6/116	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16844 AN: 151998 Hom.: 1271 Cov.: 32

Gnomad AFR AF: 0.211

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.120

Gnomad ASJ AF: 0.0530

Gnomad EAS AF: 0.0521

Gnomad SAS AF: 0.0387

Gnomad FIN AF: 0.0375

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0734

Gnomad OTH AF: 0.0891

GnomAD3 exomes AF: 0.0847 AC: 21015 AN: 248130 Hom.: 1267 AF XY: 0.0776 AC XY: 10454 AN XY: 134764

Gnomad AFR exome AF: 0.222

Gnomad AMR exome AF: 0.165

Gnomad ASJ exome AF: 0.0515

Gnomad EAS exome AF: 0.0414

Gnomad SAS exome AF: 0.0392

Gnomad FIN exome AF: 0.0432

Gnomad NFE exome AF: 0.0717

Gnomad OTH exome AF: 0.0738

GnomAD4 exome AF: 0.0761 AC: 108526 AN: 1426578 Hom.: 4963 Cov.: 27 AF XY: 0.0738 AC XY: 52550 AN XY: 711984

Gnomad4 AFR exome AF: 0.221

Gnomad4 AMR exome AF: 0.158

Gnomad4 ASJ exome AF: 0.0515

Gnomad4 EAS exome AF: 0.0734

Gnomad4 SAS exome AF: 0.0377

Gnomad4 FIN exome AF: 0.0434

Gnomad4 NFE exome AF: 0.0741

Gnomad4 OTH exome AF: 0.0729

GnomAD4 genome AF: 0.111 AC: 16870 AN: 152116 Hom.: 1276 Cov.: 32 AF XY: 0.108 AC XY: 8009 AN XY: 74400

Gnomad4 AFR AF: 0.212

Gnomad4 AMR AF: 0.120

Gnomad4 ASJ AF: 0.0530

Gnomad4 EAS AF: 0.0519

Gnomad4 SAS AF: 0.0383

Gnomad4 FIN AF: 0.0375

Gnomad4 NFE AF: 0.0734

Gnomad4 OTH AF: 0.0882

Alfa AF: 0.0801 Hom.: 198

Bravo AF: 0.124

Asia WGS AF: 0.0600 AC: 210 AN: 3478

EpiCase AF: 0.0685

EpiControl AF: 0.0644

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

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
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. -

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	-0.46
CADD	Benign	10
DANN	Benign	0.81

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: rs33976862; hg19: chr14-64408852; COSMIC: COSV58359815;