rs200742016

Positions:

• chr14-64053143-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_182914.3(SYNE2):​c.9230C>T​(p.Pro3077Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00252 in 1,614,022 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P3077P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (10 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 3.56

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013399363).
• BP6: Variant 14-64053143-C-T is Benign according to our data. Variant chr14-64053143-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197603.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, Uncertain_significance=1}. Variant chr14-64053143-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00168 (255/152226) while in subpopulation NFE AF= 0.00304 (207/68024). AF 95% confidence interval is 0.0027. There are 0 homozygotes in gnomad4. There are 117 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 255 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.9230C>T	p.Pro3077Leu	missense_variant	48/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.9230C>T	p.Pro3077Leu	missense_variant	48/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 255 AN: 152110 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000459

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.000661

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00304

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00135 AC: 336 AN: 249152 Hom.: 1 AF XY: 0.00143 AC XY: 193 AN XY: 135340

Gnomad AFR exome AF: 0.000583

Gnomad AMR exome AF: 0.000522

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.000696

Gnomad NFE exome AF: 0.00243

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00260 AC: 3807 AN: 1461796 Hom.: 10 Cov.: 37 AF XY: 0.00260 AC XY: 1893 AN XY: 727192

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000533

Gnomad4 FIN exome AF: 0.000880

Gnomad4 NFE exome AF: 0.00320

Gnomad4 OTH exome AF: 0.00192

GnomAD4 genome AF: 0.00168 AC: 255 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.00157 AC XY: 117 AN XY: 74418

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.000661

Gnomad4 NFE AF: 0.00304

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00249 Hom.: 1

Bravo AF: 0.00156

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00110 AC: 4

ESP6500EA AF: 0.00196 AC: 16

ExAC AF: 0.00121 AC: 146

EpiCase AF: 0.00294

EpiControl AF: 0.00219

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 18, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SYNE2: BP4, BS1 -

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

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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 02, 2018

- -

SYNE2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 04, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Benign	0.97
Eigen	Benign	-0.012
Eigen_PC	Benign	-0.047
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.81	T;T;T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.013	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.0	M;.;M;.
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-2.6	D;.;D;D
REVEL	Benign	0.14
Sift	Uncertain	0.011	D;.;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.99	D;.;D;.
Vest4		0.34
MVP		0.58
MPC		0.18
ClinPred		0.032	T
GERP RS		4.8
Varity_R		0.12
gMVP		0.13

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: rs200742016; hg19: chr14-64519861; COSMIC: COSV100648716; COSMIC: COSV100648716;