rs117070973

chr14-64186428-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_182914.3(SYNE2):c.17561T>C(p.Leu5854Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00638 in 1,614,206 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L5854I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0051 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (53 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.39

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]

ESR2 (HGNC:3468): (estrogen receptor 2) This gene encodes a member of the family of estrogen receptors and superfamily of nuclear receptor transcription factors. The gene product contains an N-terminal DNA binding domain and C-terminal ligand binding domain and is localized to the nucleus, cytoplasm, and mitochondria. Upon binding to 17beta-estradiol or related ligands, the encoded protein forms homo- or hetero-dimers that interact with specific DNA sequences to activate transcription. Some isoforms dominantly inhibit the activity of other estrogen receptor family members. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been fully characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008620858).
• BP6: Variant 14-64186428-T-C is Benign according to our data. Variant chr14-64186428-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 199247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64186428-T-C is described in Lovd as [Likely_benign]. Variant chr14-64186428-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00505 (770/152342) while in subpopulation NFE AF= 0.00817 (556/68028). AF 95% confidence interval is 0.00761. There are 3 homozygotes in gnomad4. There are 397 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 770 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.17561T>C	p.Leu5854Pro	missense_variant	97/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.17561T>C	p.Leu5854Pro	missense_variant	97/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.00506 AC: 770 AN: 152224 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00923

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00817

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00515 AC: 1296 AN: 251496 Hom.: 12 AF XY: 0.00507 AC XY: 689 AN XY: 135922

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00287

Gnomad FIN exome AF: 0.0104

Gnomad NFE exome AF: 0.00773

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00651 AC: 9524 AN: 1461864 Hom.: 53 Cov.: 32 AF XY: 0.00636 AC XY: 4622 AN XY: 727244

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.000650

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00270

Gnomad4 FIN exome AF: 0.00983

Gnomad4 NFE exome AF: 0.00749

Gnomad4 OTH exome AF: 0.00487

GnomAD4 genome AF: 0.00505 AC: 770 AN: 152342 Hom.: 3 Cov.: 32 AF XY: 0.00533 AC XY: 397 AN XY: 74492

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00340

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00923

Gnomad4 NFE AF: 0.00817

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00645 Hom.: 3

Bravo AF: 0.00388

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.0117 AC: 45

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00605 AC: 52

ExAC AF: 0.00574 AC: 697

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00583

EpiControl AF: 0.00658

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 14, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	SYNE2: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Benign:3

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	Invitae	Jan 08, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 06, 2016	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 27, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 05, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
Cadd	Benign	23
Dann	Pathogenic	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.84	T;T;T
MetaRNN	Benign	0.0086	T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Pathogenic	3.0	M;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-6.3	D;D;D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.99	D;D;.
Vest4		0.85
MVP		0.63
MPC		0.39
ClinPred		0.034	T
GERP RS		5.7
Varity_R		0.91
gMVP		0.70

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: rs117070973; hg19: chr14-64653146; COSMIC: COSV59951050;