rs61747118

Positions:

• chr14-64113357-T-C
• chr14-64113357-T-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.12626T>C​(p.Ile4209Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0172 in 1,613,922 control chromosomes in the GnomAD database, including 278 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I4209V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.023 (48 hom., cov: 32)
  • Exomes 𝑓: 0.017 (230 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.468

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=0.002542466).
• BP6: Variant 14-64113357-T-C is Benign according to our data. Variant chr14-64113357-T-C is described in ClinVar as [Benign]. Clinvar id is 130467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64113357-T-C is described in Lovd as [Benign]. Variant chr14-64113357-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0226 (3443/152272) while in subpopulation AFR AF= 0.0374 (1556/41556). AF 95% confidence interval is 0.0359. There are 48 homozygotes in gnomad4. There are 1705 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3443 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.12626T>C	p.Ile4209Thr	missense_variant	66/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.12626T>C	p.Ile4209Thr	missense_variant	66/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.0226 AC: 3434 AN: 152154 Hom.: 48 Cov.: 32

Gnomad AFR AF: 0.0374

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.0190

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0226

Gnomad FIN AF: 0.0285

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0153

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.0168 AC: 4228 AN: 251444 Hom.: 48 AF XY: 0.0172 AC XY: 2336 AN XY: 135906

Gnomad AFR exome AF: 0.0389

Gnomad AMR exome AF: 0.00740

Gnomad ASJ exome AF: 0.0181

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0227

Gnomad FIN exome AF: 0.0253

Gnomad NFE exome AF: 0.0157

Gnomad OTH exome AF: 0.0194

GnomAD4 exome AF: 0.0166 AC: 24251 AN: 1461650 Hom.: 230 Cov.: 32 AF XY: 0.0167 AC XY: 12135 AN XY: 727112

Gnomad4 AFR exome AF: 0.0385

Gnomad4 AMR exome AF: 0.00780

Gnomad4 ASJ exome AF: 0.0184

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0220

Gnomad4 FIN exome AF: 0.0258

Gnomad4 NFE exome AF: 0.0158

Gnomad4 OTH exome AF: 0.0193

GnomAD4 genome AF: 0.0226 AC: 3443 AN: 152272 Hom.: 48 Cov.: 32 AF XY: 0.0229 AC XY: 1705 AN XY: 74460

Gnomad4 AFR AF: 0.0374

Gnomad4 AMR AF: 0.0189

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0226

Gnomad4 FIN AF: 0.0285

Gnomad4 NFE AF: 0.0153

Gnomad4 OTH AF: 0.0189

Alfa AF: 0.0151 Hom.: 30

Bravo AF: 0.0222

TwinsUK AF: 0.0151 AC: 56

ALSPAC AF: 0.0145 AC: 56

ESP6500AA AF: 0.0347 AC: 153

ESP6500EA AF: 0.0158 AC: 136

ExAC AF: 0.0171 AC: 2075

Asia WGS AF: 0.0190 AC: 66 AN: 3478

EpiCase AF: 0.0161

EpiControl AF: 0.0138

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 19, 2019	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	7.3
DANN	Benign	0.52
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.096	N
LIST_S2	Benign	0.60	T;T;T;T;T
MetaRNN	Benign	0.0025	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.7	N;.;N;N;N
REVEL	Benign	0.076
Sift	Benign	0.13	T;.;T;T;T
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		0.0040	B;.;B;.;.
Vest4		0.13
MPC		0.058
ClinPred		0.0025	T
GERP RS		2.0
Varity_R		0.040
gMVP		0.11

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: rs61747118; hg19: chr14-64580075;