rs780632525

Positions:

• chr14-64065605-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_182914.3(SYNE2):​c.10386G>A​(p.Met3462Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.245

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.082889944).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.10386G>A	p.Met3462Ile	missense_variant	51/116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.10386G>A	p.Met3462Ile	missense_variant	51/116	1	NM_182914.3	ENSP00000450831	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249510 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135354

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461854 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000827 AC: 1

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

Oct 16, 2016

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 isoleucine 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. This variant is present in population databases (rs780632525, ExAC 0.006%) but has not been reported in the literature in individuals with a SYNE2-related disease. This sequence change replaces methionine with isoleucine at codon 3462 of the SYNE2 protein (p.Met3462Ile). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and isoleucine. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.030	.;T;T;T;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.78	T;T;T;T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.083	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;.;L;.;.
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.0	N;.;N;N;N
REVEL	Benign	0.024
Sift	Benign	0.11	T;.;T;T;T
Sift4G	Benign	0.48	T;T;T;T;T
Polyphen		0.0040	B;.;B;.;.
Vest4		0.15
MutPred		0.38		Gain of catalytic residue at L3467 (P = 0.078);.;Gain of catalytic residue at L3467 (P = 0.078);.;.;
MVP		0.36
MPC		0.051
ClinPred		0.087	T
GERP RS		3.7
Varity_R		0.11
gMVP		0.050

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: rs780632525; hg19: chr14-64532323;