rs984046422

Variant names:

• chr14-64048032-A-C
• rs984046422
• NM_182914.3:c.7254A>C

Your query was ambiguous. Multiple possible variants found:

• chr14-64048032-A-C
• chr14-64048032-A-G

Variant summary

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

The NM_182914.3(SYNE2):​c.7254A>C​(p.Gln2418His) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.379

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=0.13846743).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.7254A>C	p.Gln2418His	missense_variant	Exon 46 of 116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.7254A>C	p.Gln2418His	missense_variant	Exon 46 of 116	1	NM_182914.3	ENSP00000450831.2

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

Submissions by phenotype

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

Jul 20, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamine with histidine at codon 2418 of the SYNE2 protein (p.Gln2418His). The glutamine residue is weakly conserved and there is a small physicochemical difference between glutamine and histidine. 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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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	0.21
BayesDel_addAF	Benign	-0.054	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	.;T;T;T
Eigen	Benign	0.085
Eigen_PC	Benign	0.048
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.80	T;T;T;T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	2.0	M;.;M;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.9	N;D;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.25
MutPred		0.14		Loss of helix (P = 0.2022);.;Loss of helix (P = 0.2022);.;
MVP		0.39
MPC		0.32
ClinPred		0.80	D
GERP RS		2.0
Varity_R		0.12
gMVP		0.31

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: rs984046422; hg19: chr14-64514750;