rs540706990

chr14-64052762-A-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_182914.3(SYNE2):c.8849A>C(p.Glu2950Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,612,332 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.49

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 Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11928645).
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000329 (48/1460086) while in subpopulation AFR AF= 0.00003 (1/33322). AF 95% confidence interval is 0.0000166. There are 0 homozygotes in gnomad4_exome. There are 29 alleles in male gnomad4_exome subpopulation. Median coverage is 37. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.8849A>C	p.Glu2950Ala	missense_variant	48/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.8849A>C	p.Glu2950Ala	missense_variant	48/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000403 AC: 10 AN: 247972 Hom.: 0 AF XY: 0.0000372 AC XY: 5 AN XY: 134588

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000326

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000329 AC: 48 AN: 1460086 Hom.: 0 Cov.: 37 AF XY: 0.0000399 AC XY: 29 AN XY: 726186

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.0000664

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152246 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74386

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.0000331 AC: 4

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

Jul 19, 2017

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 do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SYNE2-related disease. This variant is present in population databases (rs540706990, ExAC 0.03%). This sequence change replaces glutamic acid with alanine at codon 2950 of the SYNE2 protein (p.Glu2950Ala). The glutamic acid residue is weakly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	19
Dann	Benign	0.93
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.2	M;.;M;.
MutationTaster	Benign	0.99	D;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.4	D;D;D;D
REVEL	Benign	0.097
Sift	Uncertain	0.020	D;D;D;T
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		0.13	B;.;B;.
Vest4		0.34
MVP		0.41
MPC		0.30
ClinPred		0.27	T
GERP RS		4.1
Varity_R		0.11
gMVP		0.099

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: rs540706990; hg19: chr14-64519480;