14-64003284-A-G

Position:

• chr14-64003284-A-G

Variant summary

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

The ENST00000555002.6(SYNE2):​c.4351A>G​(p.Ser1451Gly) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYNE2 ENST00000555002.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.789

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 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=0.07150492).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.4351A>G	p.Ser1451Gly	missense_variant	30/116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.4351A>G	p.Ser1451Gly	missense_variant	30/116	1	NM_182914.3	ENSP00000450831	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Labcorp Genetics (formerly Invitae), Labcorp

May 12, 2018

This sequence change replaces serine with glycine at codon 1451 of the SYNE2 protein (p.Ser1451Gly). The serine residue is weakly conserved and there is a small physicochemical difference between serine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SYNE2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.91
DEOGEN2	Benign	0.025	.;T;T;T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.68	T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.072	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L;.;L;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.5	N;.;N;N
REVEL	Benign	0.015
Sift	Benign	0.40	T;.;T;T
Sift4G	Benign	0.33	T;T;T;T
Polyphen		0.0040	B;.;B;.
Vest4		0.094
MutPred		0.30		Loss of stability (P = 0.0338);Loss of stability (P = 0.0338);Loss of stability (P = 0.0338);Loss of stability (P = 0.0338);
MVP		0.31
MPC		0.046
ClinPred		0.12	T
GERP RS		3.5
Varity_R		0.058
gMVP		0.062

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: rs535438406; hg19: chr14-64470002;