rs34820571

Positions:

• chr14-64220587-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.20011G>A​(p.Ala6671Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00415 in 1,614,166 control chromosomes in the GnomAD database, including 21 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (18 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.217

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=0.004609406).
• BP6: Variant 14-64220587-G-A is Benign according to our data. Variant chr14-64220587-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 193953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64220587-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00325 (495/152286) while in subpopulation NFE AF= 0.00481 (327/68020). AF 95% confidence interval is 0.00438. There are 3 homozygotes in gnomad4. There are 248 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 495 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.20011G>A	p.Ala6671Thr	missense_variant	111/116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.20011G>A	p.Ala6671Thr	missense_variant	111/116	1	NM_182914.3	ENSP00000450831	P4

Frequencies

GnomAD3 genomes AF: 0.00325 AC: 495 AN: 152168 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00751

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00622

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00479

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00338 AC: 848 AN: 250932 Hom.: 2 AF XY: 0.00335 AC XY: 455 AN XY: 135704

Gnomad AFR exome AF: 0.000616

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.00815

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.00725

Gnomad NFE exome AF: 0.00449

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00425 AC: 6210 AN: 1461880 Hom.: 18 Cov.: 31 AF XY: 0.00422 AC XY: 3072 AN XY: 727240

Gnomad4 AFR exome AF: 0.000956

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.00815

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000927

Gnomad4 FIN exome AF: 0.00788

Gnomad4 NFE exome AF: 0.00465

Gnomad4 OTH exome AF: 0.00341

GnomAD4 genome AF: 0.00325 AC: 495 AN: 152286 Hom.: 3 Cov.: 32 AF XY: 0.00333 AC XY: 248 AN XY: 74460

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00751

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00622

Gnomad4 NFE AF: 0.00481

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00467 Hom.: 3

Bravo AF: 0.00259

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00581 AC: 50

ExAC AF: 0.00346 AC: 420

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00431

EpiControl AF: 0.00528

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Benign:4

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	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Jan 13, 2016	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	SYNE2: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 17, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.8
DANN	Benign	0.68
DEOGEN2	Benign	0.034	.;T;T;T;T;.;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.58	T;T;T;T;T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0046	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	.;.;M;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.2	N;.;N;N;N;N;.
REVEL	Benign	0.0080
Sift	Benign	0.37	T;.;T;T;T;T;.
Sift4G	Benign	0.45	T;T;T;T;T;T;.
Polyphen		0.38	B;.;P;B;.;B;P
Vest4		0.16
MVP		0.28
MPC		0.050
ClinPred		0.0082	T
GERP RS		0.56
Varity_R		0.051
gMVP		0.078

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: rs34820571; hg19: chr14-64687305;