rs45453691

Positions:

• chr14-64218494-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_182914.3(SYNE2):​c.19639A>G​(p.Ile6547Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 1,613,956 control chromosomes in the GnomAD database, including 235 homozygotes. 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I6547I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.010 (15 hom., cov: 32)
  • Exomes 𝑓: 0.014 (220 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.76

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025786757).
• BP6: Variant 14-64218494-A-G is Benign according to our data. Variant chr14-64218494-A-G is described in ClinVar as [Benign]. Clinvar id is 313653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64218494-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0105 (1598/152326) while in subpopulation SAS AF= 0.023 (111/4826). AF 95% confidence interval is 0.0195. There are 15 homozygotes in gnomad4. There are 730 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1598 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.19639A>G	p.Ile6547Val	missense_variant	109/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.19639A>G	p.Ile6547Val	missense_variant	109/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1598 AN: 152208 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.00273

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.00968

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0230

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0144

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0136 AC: 3400 AN: 250920 Hom.: 45 AF XY: 0.0149 AC XY: 2024 AN XY: 135614

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.00662

Gnomad ASJ exome AF: 0.0428

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0269

Gnomad FIN exome AF: 0.00308

Gnomad NFE exome AF: 0.0152

Gnomad OTH exome AF: 0.0139

GnomAD4 exome AF: 0.0141 AC: 20569 AN: 1461630 Hom.: 220 Cov.: 31 AF XY: 0.0148 AC XY: 10738 AN XY: 727104

Gnomad4 AFR exome AF: 0.00170

Gnomad4 AMR exome AF: 0.00686

Gnomad4 ASJ exome AF: 0.0438

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0281

Gnomad4 FIN exome AF: 0.00306

Gnomad4 NFE exome AF: 0.0139

Gnomad4 OTH exome AF: 0.0148

GnomAD4 genome AF: 0.0105 AC: 1598 AN: 152326 Hom.: 15 Cov.: 32 AF XY: 0.00980 AC XY: 730 AN XY: 74494

Gnomad4 AFR AF: 0.00272

Gnomad4 AMR AF: 0.00967

Gnomad4 ASJ AF: 0.0421

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0230

Gnomad4 FIN AF: 0.00395

Gnomad4 NFE AF: 0.0144

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.0156 Hom.: 57

Bravo AF: 0.0107

TwinsUK AF: 0.0140 AC: 52

ALSPAC AF: 0.0138 AC: 53

ESP6500AA AF: 0.00340 AC: 15

ESP6500EA AF: 0.0149 AC: 128

ExAC AF: 0.0135 AC: 1643

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0174

EpiControl AF: 0.0163

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 19, 2020	- -

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 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. -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.044
DANN	Benign	0.26
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.45	T;T;T;T;T;T
MetaRNN	Benign	0.0026	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.27	N;N;N;.;N;.
REVEL	Benign	0.0040
Sift	Benign	0.47	T;T;T;.;T;.
Sift4G	Benign	1.0	T;T;T;.;T;.
Polyphen		0.0020	B;B;.;.;B;B
Vest4		0.074
MPC		0.042
ClinPred		0.00055	T
GERP RS		-6.5
Varity_R		0.014
gMVP		0.13

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: rs45453691; hg19: chr14-64685212;