14-63853152-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_182914.3(SYNE2):c.-52+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00743 in 151,698 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0074 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0083 (0 hom.)
• Consequence: SYNE2 NM_182914.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.19

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 14-63853152-G-A is Benign according to our data. Variant chr14-63853152-G-A is described in ClinVar as [Benign]. Clinvar id is 313481.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-63853152-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00743 (1126/151578) while in subpopulation AMR AF= 0.0169 (258/15232). AF 95% confidence interval is 0.0152. There are 6 homozygotes in gnomad4. There are 541 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1128 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.-52+9G>A		intron_variant		ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.-52+9G>A		intron_variant		1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.00745 AC: 1128 AN: 151470 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0170

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000478

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00961

GnomAD4 exome AF: 0.00833 AC: 1 AN: 120 Hom.: 0 Cov.: 0 AF XY: 0.0109 AC XY: 1 AN XY: 92

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.00943

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00743 AC: 1126 AN: 151578 Hom.: 6 Cov.: 32 AF XY: 0.00730 AC XY: 541 AN XY: 74086

Gnomad4 AFR AF: 0.00181

Gnomad4 AMR AF: 0.0169

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000478

Gnomad4 NFE AF: 0.0101

Gnomad4 OTH AF: 0.00951

Alfa AF: 0.00225 Hom.: 0

Bravo AF: 0.00834

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	18
Dann	Uncertain	0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs535493323; hg19: chr14-64319870;