rs17179194

Positions:

• chr14-64167266-G-A

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.16639G>A​(p.Asp5547Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0137 in 1,614,194 control chromosomes in the GnomAD database, including 225 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D5547G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (13 hom., cov: 32)
  • Exomes 𝑓: 0.014 (212 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.65

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=0.0024761856).
• BP6: Variant 14-64167266-G-A is Benign according to our data. Variant chr14-64167266-G-A is described in ClinVar as [Benign]. Clinvar id is 313627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64167266-G-A is described in Lovd as [Benign]. Variant chr14-64167266-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0105 (1594/152318) while in subpopulation SAS AF= 0.0228 (110/4824). AF 95% confidence interval is 0.0193. There are 13 homozygotes in gnomad4. There are 713 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1594 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.16639G>A	p.Asp5547Asn	missense_variant	91/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.16639G>A	p.Asp5547Asn	missense_variant	91/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.0105 AC: 1593 AN: 152200 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00384

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.0449

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0228

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0141

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.0132 AC: 3312 AN: 251298 Hom.: 39 AF XY: 0.0143 AC XY: 1947 AN XY: 135816

Gnomad AFR exome AF: 0.00345

Gnomad AMR exome AF: 0.00616

Gnomad ASJ exome AF: 0.0457

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0243

Gnomad FIN exome AF: 0.00291

Gnomad NFE exome AF: 0.0149

Gnomad OTH exome AF: 0.0135

GnomAD4 exome AF: 0.0140 AC: 20453 AN: 1461876 Hom.: 212 Cov.: 30 AF XY: 0.0145 AC XY: 10536 AN XY: 727242

Gnomad4 AFR exome AF: 0.00236

Gnomad4 AMR exome AF: 0.00642

Gnomad4 ASJ exome AF: 0.0460

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0255

Gnomad4 FIN exome AF: 0.00328

Gnomad4 NFE exome AF: 0.0140

Gnomad4 OTH exome AF: 0.0144

GnomAD4 genome AF: 0.0105 AC: 1594 AN: 152318 Hom.: 13 Cov.: 32 AF XY: 0.00957 AC XY: 713 AN XY: 74478

Gnomad4 AFR AF: 0.00385

Gnomad4 AMR AF: 0.00758

Gnomad4 ASJ AF: 0.0449

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0228

Gnomad4 FIN AF: 0.00348

Gnomad4 NFE AF: 0.0141

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0157 Hom.: 64

Bravo AF: 0.0105

TwinsUK AF: 0.0132 AC: 49

ALSPAC AF: 0.0130 AC: 50

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0149 AC: 128

ExAC AF: 0.0132 AC: 1597

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.0176

EpiControl AF: 0.0160

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 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 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	0.093
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Uncertain	1.0
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.78	T;T;T;T;T
MetaRNN	Benign	0.0025	T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.4	M;.;M;.;.
MutationTaster	Benign	1.0	D;N;N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-4.2	D;.;D;D;D
REVEL	Benign	0.16
Sift	Uncertain	0.0030	D;.;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D
Polyphen		0.78	P;.;P;B;.
Vest4		0.13
MPC		0.050
ClinPred		0.052	T
GERP RS		4.9
Varity_R		0.30
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17179194; hg19: chr14-64633984;