rs149391344

chr14-64081475-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_182914.3(SYNE2):c.11379T>C(p.Leu3793=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00402 in 1,614,176 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (18 hom.)
• Consequence: SYNE2 NM_182914.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.290

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 14-64081475-T-C is Benign according to our data. Variant chr14-64081475-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 282477.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00313 (476/152296) while in subpopulation NFE AF= 0.00466 (317/68024). AF 95% confidence interval is 0.00424. There are 6 homozygotes in gnomad4. There are 219 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 477 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.11379T>C	p.Leu3793=	synonymous_variant	57/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.11379T>C	p.Leu3793=	synonymous_variant	57/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.00313 AC: 477 AN: 152178 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00612

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00466

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00356 AC: 895 AN: 251464 Hom.: 5 AF XY: 0.00326 AC XY: 443 AN XY: 135906

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.00833

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.00721

Gnomad NFE exome AF: 0.00404

Gnomad OTH exome AF: 0.00619

GnomAD4 exome AF: 0.00411 AC: 6010 AN: 1461880 Hom.: 18 Cov.: 32 AF XY: 0.00404 AC XY: 2939 AN XY: 727236

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00309

Gnomad4 ASJ exome AF: 0.00754

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00152

Gnomad4 FIN exome AF: 0.00786

Gnomad4 NFE exome AF: 0.00431

Gnomad4 OTH exome AF: 0.00422

GnomAD4 genome AF: 0.00313 AC: 476 AN: 152296 Hom.: 6 Cov.: 32 AF XY: 0.00294 AC XY: 219 AN XY: 74474

Gnomad4 AFR AF: 0.000625

Gnomad4 AMR AF: 0.00190

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00612

Gnomad4 NFE AF: 0.00466

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00422 Hom.: 1

Bravo AF: 0.00268

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00403

EpiControl AF: 0.00468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 17, 2015

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

SYNE2: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	4.6
Dann	Benign	0.64

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: rs149391344; hg19: chr14-64548193;