rs200437377

chr14-64000587-G-Achr14-64000587-G-T

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.3506G>A(p.Arg1169His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000949 in 1,613,294 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1169C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (1 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 0.167

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=0.036743402).
• BP6: Variant 14-64000587-G-A is Benign according to our data. Variant chr14-64000587-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282514.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000532 (81/152212) while in subpopulation NFE AF= 0.000926 (63/68012). AF 95% confidence interval is 0.000742. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 81 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.3506G>A	p.Arg1169His	missense_variant	28/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.3506G>A	p.Arg1169His	missense_variant	28/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.000533 AC: 81 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000494 AC: 123 AN: 249150 Hom.: 1 AF XY: 0.000525 AC XY: 71 AN XY: 135198

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000920

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000992 AC: 1450 AN: 1461082 Hom.: 1 Cov.: 31 AF XY: 0.000985 AC XY: 716 AN XY: 726856

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.00122

Gnomad4 OTH exome AF: 0.000812

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35 AN XY: 74412

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000926

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000913 Hom.: 1

Bravo AF: 0.000521

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000556 AC: 2

ESP6500EA AF: 0.00111 AC: 9

ExAC AF: 0.000422 AC: 51

EpiCase AF: 0.00115

EpiControl AF: 0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 12, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 19, 2023	- -
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. -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 25, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 16, 2024	The c.3506G>A (p.R1169H) alteration is located in exon 28 (coding exon 27) of the SYNE2 gene. This alteration results from a G to A substitution at nucleotide position 3506, causing the arginine (R) at amino acid position 1169 to be replaced by a histidine (H). 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)

Aug 07, 2015

- -

SYNE2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 10, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	6.7
Dann	Benign	0.26
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.20	T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.037	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N;.;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.10	N;.;N;N
REVEL	Benign	0.027
Sift	Benign	0.51	T;.;T;T
Sift4G	Benign	0.59	T;T;T;T
Polyphen		0.0	B;.;B;.
Vest4		0.17
MVP		0.36
MPC		0.055
ClinPred		0.0015	T
GERP RS		-1.6
Varity_R		0.021
gMVP		0.062

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: rs200437377; hg19: chr14-64467305; COSMIC: COSV59941496; COSMIC: COSV59941496;