rs201176149

chr14-63976588-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_182914.3(SYNE2):c.1154A>G(p.Asn385Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000352 in 1,608,268 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 6.06

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009871334).
• BP6: Variant 14-63976588-A-G is Benign according to our data. Variant chr14-63976588-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 283981.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=1, Benign=1}. Variant chr14-63976588-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000413 (61/147598) while in subpopulation AMR AF= 0.000612 (9/14696). AF 95% confidence interval is 0.000319. There are 0 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 60 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.1154A>G	p.Asn385Ser	missense_variant	12/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.1154A>G	p.Asn385Ser	missense_variant	12/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.000407 AC: 60 AN: 147516 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000613

Gnomad ASJ AF: 0.00636

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000385

Gnomad OTH AF: 0.000986

GnomAD3 exomes AF: 0.000334 AC: 83 AN: 248570 Hom.: 0 AF XY: 0.000341 AC XY: 46 AN XY: 134906

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00250

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000293

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.000346 AC: 505 AN: 1460670 Hom.: 0 Cov.: 37 AF XY: 0.000322 AC XY: 234 AN XY: 726630

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000448

Gnomad4 ASJ exome AF: 0.00387

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000307

Gnomad4 OTH exome AF: 0.000647

GnomAD4 genome AF: 0.000413 AC: 61 AN: 147598 Hom.: 0 Cov.: 28 AF XY: 0.000404 AC XY: 29 AN XY: 71788

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000612

Gnomad4 ASJ AF: 0.00636

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000426

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000385

Gnomad4 OTH AF: 0.000978

Alfa AF: 0.000512 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000489 AC: 4

ExAC AF: 0.000240 AC: 29

EpiCase AF: 0.000654

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 14, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.1154A>G (p.N385S) alteration is located in exon 12 (coding exon 11) of the SYNE2 gene. This alteration results from a A to G substitution at nucleotide position 1154, causing the asparagine (N) at amino acid position 385 to be replaced by a serine (S). 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

Eurofins Ntd Llc (ga)

Oct 13, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	17
Dann	Benign	0.95
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0099	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.3	M;.;M;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.7	N;.;N;N
REVEL	Benign	0.10
Sift	Uncertain	0.0080	D;.;D;D
Sift4G	Uncertain	0.016	D;D;D;D
Polyphen		0.017	B;.;B;.
Vest4		0.27
MVP		0.32
MPC		0.061
ClinPred		0.048	T
GERP RS		4.0
Varity_R		0.090
gMVP		0.095

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: rs201176149; hg19: chr14-64443306;