rs150644129

chr14-64224488-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.20410G>A(p.Asp6804Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00329 in 1,614,008 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0034 (18 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:7
• Conservation: PhyloP100: 2.08

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=0.0050381124).
• BP6: Variant 14-64224488-G-A is Benign according to our data. Variant chr14-64224488-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 193956.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64224488-G-A is described in Lovd as [Likely_benign]. Variant chr14-64224488-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00251 (382/152182) while in subpopulation NFE AF= 0.00375 (255/68006). AF 95% confidence interval is 0.00337. There are 1 homozygotes in gnomad4. There are 166 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 382 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.20410G>A	p.Asp6804Asn	missense_variant	114/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.20410G>A	p.Asp6804Asn	missense_variant	114/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.00251 AC: 382 AN: 152064 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.0260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00375

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00284 AC: 714 AN: 251466 Hom.: 5 AF XY: 0.00290 AC XY: 394 AN XY: 135912

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.0239

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00353

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00338 AC: 4936 AN: 1461826 Hom.: 18 Cov.: 32 AF XY: 0.00336 AC XY: 2443 AN XY: 727218

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.0242

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000290

Gnomad4 FIN exome AF: 0.000487

Gnomad4 NFE exome AF: 0.00356

Gnomad4 OTH exome AF: 0.00383

GnomAD4 genome AF: 0.00251 AC: 382 AN: 152182 Hom.: 1 Cov.: 31 AF XY: 0.00223 AC XY: 166 AN XY: 74382

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.0260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00375

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00432 Hom.: 7

Bravo AF: 0.00227

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.00236 AC: 287

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:7

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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Dec 09, 2015	- -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SYNE2: BP4, BS1:Supporting, BS2 -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 22, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	19
Dann	Benign	0.65
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.13	N
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.0050	T;T;T;T;T;T;T
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	0.91	N;N;N;N;N;N;N;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-4.3	D;.;D;D;D;D;.
REVEL	Benign	0.085
Sift	Uncertain	0.011	D;.;D;D;D;D;.
Sift4G	Uncertain	0.025	D;D;D;D;D;T;.
Polyphen		1.0	D;.;D;B;.;D;D
Vest4		0.36
MVP		0.53
MPC		0.32
ClinPred		0.049	T
GERP RS		3.8
Varity_R		0.10
gMVP		0.26

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: rs150644129; hg19: chr14-64691206; COSMIC: COSV59954515; COSMIC: COSV59954515;