rs117567094

Positions:

• chr14-63978927-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_182914.3(SYNE2):​c.1482G>A​(p.Leu494=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00905 in 1,612,710 control chromosomes in the GnomAD database, including 95 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0093 (86 hom.)
• Consequence: SYNE2 NM_182914.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.440

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 14-63978927-G-A is Benign according to our data. Variant chr14-63978927-G-A is described in ClinVar as [Benign]. Clinvar id is 313488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.44 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00659 (1003/152284) while in subpopulation SAS AF= 0.012 (58/4820). AF 95% confidence interval is 0.00956. There are 9 homozygotes in gnomad4. There are 499 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1003 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.1482G>A	p.Leu494=	synonymous_variant	14/116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.1482G>A	p.Leu494=	synonymous_variant	14/116	1	NM_182914.3	ENSP00000450831	P4

Frequencies

GnomAD3 genomes AF: 0.00662 AC: 1008 AN: 152166 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00569

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0126

Gnomad FIN AF: 0.00538

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0102

Gnomad OTH AF: 0.00910

GnomAD3 exomes AF: 0.00781 AC: 1948 AN: 249420 Hom.: 10 AF XY: 0.00891 AC XY: 1206 AN XY: 135326

Gnomad AFR exome AF: 0.00239

Gnomad AMR exome AF: 0.00203

Gnomad ASJ exome AF: 0.00358

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0142

Gnomad FIN exome AF: 0.00516

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.00711

GnomAD4 exome AF: 0.00931 AC: 13590 AN: 1460426 Hom.: 86 Cov.: 30 AF XY: 0.00958 AC XY: 6959 AN XY: 726612

Gnomad4 AFR exome AF: 0.00161

Gnomad4 AMR exome AF: 0.00228

Gnomad4 ASJ exome AF: 0.00287

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0146

Gnomad4 FIN exome AF: 0.00600

Gnomad4 NFE exome AF: 0.0101

Gnomad4 OTH exome AF: 0.00792

GnomAD4 genome AF: 0.00659 AC: 1003 AN: 152284 Hom.: 9 Cov.: 32 AF XY: 0.00670 AC XY: 499 AN XY: 74454

Gnomad4 AFR AF: 0.00195

Gnomad4 AMR AF: 0.00569

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0120

Gnomad4 FIN AF: 0.00538

Gnomad4 NFE AF: 0.0102

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00821 Hom.: 4

Bravo AF: 0.00592

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.0106

EpiControl AF: 0.00942

ClinVar

Significance: Benign

Submissions summary: Benign:4

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	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SYNE2: BP4, BP7, BS1, BS2 -

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	8.2
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs117567094; hg19: chr14-64445645; COSMIC: COSV100646345;