rs140897155

Positions:

• chr14-64221675-G-A

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.20161G>A​(p.Ala6721Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,614,036 control chromosomes in the GnomAD database, including 4 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).

• Frequency:
  • Genomes: 𝑓 0.00084 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (4 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.44

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]

ESR2 (HGNC:3468): (estrogen receptor 2) This gene encodes a member of the family of estrogen receptors and superfamily of nuclear receptor transcription factors. The gene product contains an N-terminal DNA binding domain and C-terminal ligand binding domain and is localized to the nucleus, cytoplasm, and mitochondria. Upon binding to 17beta-estradiol or related ligands, the encoded protein forms homo- or hetero-dimers that interact with specific DNA sequences to activate transcription. Some isoforms dominantly inhibit the activity of other estrogen receptor family members. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been fully characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012589395).
• BP6: Variant 14-64221675-G-A is Benign according to our data. Variant chr14-64221675-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282661.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000841 (128/152172) while in subpopulation NFE AF= 0.0015 (102/68036). AF 95% confidence interval is 0.00126. There are 0 homozygotes in gnomad4. There are 68 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 128 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.20161G>A	p.Ala6721Thr	missense_variant	112/116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.20161G>A	p.Ala6721Thr	missense_variant	112/116	1	NM_182914.3	ENSP00000450831	P4

Frequencies

GnomAD3 genomes AF: 0.000841 AC: 128 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00150

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000990 AC: 249 AN: 251452 Hom.: 0 AF XY: 0.000876 AC XY: 119 AN XY: 135908

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00181

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00180 AC: 2630 AN: 1461864 Hom.: 4 Cov.: 32 AF XY: 0.00164 AC XY: 1193 AN XY: 727234

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000936

Gnomad4 NFE exome AF: 0.00223

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.000841 AC: 128 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.000915 AC XY: 68 AN XY: 74338

Gnomad4 AFR AF: 0.000338

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.00150

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00138 Hom.: 0

Bravo AF: 0.000842

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00113 AC: 137

EpiCase AF: 0.00125

EpiControl AF: 0.00113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 19, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	SYNE2: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 10, 2017	- -

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

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	- -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.4
DANN	Benign	0.59
DEOGEN2	Benign	0.0046	.;T;T;T;T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.73	T;T;T;T;T;T;T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.013	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.24	.;.;N;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	1.2	N;.;N;N;N;N;.
REVEL	Benign	0.033
Sift	Benign	1.0	T;.;T;T;T;T;.
Sift4G	Benign	0.93	T;T;T;T;T;T;.
Polyphen		0.0070	B;.;B;B;.;B;B
Vest4		0.20
MVP		0.13
MPC		0.047
ClinPred		0.0010	T
GERP RS		1.1
Varity_R		0.014
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: rs140897155; hg19: chr14-64688393;