rs373690979

chr14-64051675-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_182914.3(SYNE2):c.7762G>A(p.Val2588Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000195 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: -0.404

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.035588145).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000151 (23/152206) while in subpopulation NFE AF= 0.000309 (21/68036). AF 95% confidence interval is 0.000207. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.7762G>A	p.Val2588Met	missense_variant	48/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.7762G>A	p.Val2588Met	missense_variant	48/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000132 AC: 33 AN: 249360 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135280

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000186

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000200 AC: 292 AN: 1461862 Hom.: 0 Cov.: 30 AF XY: 0.000219 AC XY: 159 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000243

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74350

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000159 Hom.: 0

Bravo AF: 0.000128

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000244 AC: 2

ExAC AF: 0.0000993 AC: 12

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Uncertain:2 Benign:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 06, 2023	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 2588 of the SYNE2 protein (p.Val2588Met). This variant is present in population databases (rs373690979, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SYNE2-related conditions. ClinVar contains an entry for this variant (Variation ID: 376965). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 19, 2020	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 26, 2023

The c.7762G>A (p.V2588M) alteration is located in exon 48 (coding exon 47) of the SYNE2 gene. This alteration results from a G to A substitution at nucleotide position 7762, causing the valine (V) at amino acid position 2588 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Nov 08, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.66
Cadd	Benign	3.5
Dann	Benign	0.25
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.79	T;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.036	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;.;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.18	N;N;N;N
REVEL	Benign	0.019
Sift	Benign	0.047	D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;D
Polyphen		0.14	B;.;B;.
Vest4		0.090
MVP		0.21
MPC		0.051
ClinPred		0.020	T
GERP RS		0.85
Varity_R		0.022
gMVP		0.043

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: rs373690979; hg19: chr14-64518393;