rs1555551887

chr14-64214447-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_182914.3(SYNE2):c.19310G>A(p.Gly6437Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G6437S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.44

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15713885).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.19310G>A	p.Gly6437Asp	missense_variant	106/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.19310G>A	p.Gly6437Asp	missense_variant	106/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 06, 2017

This variant has not been reported in the literature in individuals with a SYNE2-related disease. In summary, this variant has uncertain impact on SYNE2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 6437 of the SYNE2 protein (p.Gly6437Asp). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	23
Dann	Benign	0.83
Eigen	Benign	-0.072
Eigen_PC	Benign	-0.071
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.79	T;T;T;T;T;T;T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.16	T;T;T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.6	L;.;L;.;.;.;.
MutationTaster	Benign	1.0	D;N;N;N;N;N;N;N;N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.9	D;.;N;N;D;.;D
REVEL	Benign	0.12
Sift	Uncertain	0.011	D;.;T;T;D;.;D
Sift4G	Uncertain	0.020	D;T;T;T;D;.;D
Polyphen		1.0	D;.;P;D;.;.;D
Vest4		0.56
MutPred		0.13		Gain of solvent accessibility (P = 0.1583);.;Gain of solvent accessibility (P = 0.1583);.;.;.;.;
MVP		0.55
MPC		0.36
ClinPred		0.76	D
GERP RS		3.4
Varity_R		0.062
gMVP		0.30

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: rs1555551887; hg19: chr14-64681165;