rs1555400535

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000555002.6(SYNE2):​c.802G>A​(p.Asp268Asn) 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. 16/21 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. D268V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

SYNE2
ENST00000555002.6 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.528
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.053038746).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SYNE2NM_182914.3 linkuse as main transcriptc.802G>A p.Asp268Asn missense_variant 9/116 ENST00000555002.6 NP_878918.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SYNE2ENST00000555002.6 linkuse as main transcriptc.802G>A p.Asp268Asn missense_variant 9/1161 NM_182914.3 ENSP00000450831 P4Q8WXH0-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 20, 2022This variant has not been reported in the literature in individuals affected with SYNE2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 268 of the SYNE2 protein (p.Asp268Asn). ClinVar contains an entry for this variant (Variation ID: 470984). 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. 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 asparagine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.068
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
14
DANN
Benign
0.49
DEOGEN2
Benign
0.0041
.;T;T;T
Eigen
Benign
-1.3
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.81
T;T;T;T
M_CAP
Benign
0.081
D
MetaRNN
Benign
0.053
T;T;T;T
MetaSVM
Benign
-0.53
T
MutationAssessor
Benign
-1.4
N;.;N;.
MutationTaster
Benign
1.0
D;N;N;N
PrimateAI
Benign
0.27
T
PROVEAN
Benign
0.76
N;.;N;N
REVEL
Benign
0.19
Sift
Benign
0.96
T;.;T;T
Sift4G
Benign
1.0
T;T;T;T
Polyphen
0.0
B;.;B;.
Vest4
0.069
MutPred
0.42
Gain of catalytic residue at D268 (P = 5e-04);Gain of catalytic residue at D268 (P = 5e-04);Gain of catalytic residue at D268 (P = 5e-04);Gain of catalytic residue at D268 (P = 5e-04);
MVP
0.51
MPC
0.047
ClinPred
0.036
T
GERP RS
0.85
Varity_R
0.033
gMVP
0.053

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555400535; hg19: chr14-64428257; API