rs17101704

Positions:

• chr14-64167349-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_182914.3(SYNE2):​c.16722A>G​(p.Gln5574Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0385 in 1,614,220 control chromosomes in the GnomAD database, including 1,394 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (202 hom., cov: 33)
  • Exomes 𝑓: 0.038 (1192 hom.)
• Consequence: SYNE2 NM_182914.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.307

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]

SYNE2 (HGNC:):

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 14-64167349-A-G is Benign according to our data. Variant chr14-64167349-A-G is described in ClinVar as [Benign]. Clinvar id is 130484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64167349-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.307 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0653 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE2	NM_182914.3	c.16722A>G	p.Gln5574Gln	synonymous_variant	91/116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6	c.16722A>G	p.Gln5574Gln	synonymous_variant	91/116	1	NM_182914.3	ENSP00000450831.2

Frequencies

GnomAD3 genomes AF: 0.0460 AC: 6998 AN: 152224 Hom.: 200 Cov.: 33

Gnomad AFR AF: 0.0673

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.0364

Gnomad ASJ AF: 0.0288

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0126

Gnomad FIN AF: 0.0490

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0402

Gnomad OTH AF: 0.0455

GnomAD3 exomes AF: 0.0351 AC: 8825 AN: 251392 Hom.: 200 AF XY: 0.0340 AC XY: 4622 AN XY: 135880

Gnomad AFR exome AF: 0.0692

Gnomad AMR exome AF: 0.0224

Gnomad ASJ exome AF: 0.0318

Gnomad EAS exome AF: 0.000979

Gnomad SAS exome AF: 0.0131

Gnomad FIN exome AF: 0.0486

Gnomad NFE exome AF: 0.0428

Gnomad OTH exome AF: 0.0434

GnomAD4 exome AF: 0.0378 AC: 55216 AN: 1461878 Hom.: 1192 Cov.: 31 AF XY: 0.0372 AC XY: 27029 AN XY: 727238

Gnomad4 AFR exome AF: 0.0749

Gnomad4 AMR exome AF: 0.0235

Gnomad4 ASJ exome AF: 0.0282

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.0141

Gnomad4 FIN exome AF: 0.0460

Gnomad4 NFE exome AF: 0.0400

Gnomad4 OTH exome AF: 0.0389

GnomAD4 genome AF: 0.0460 AC: 7008 AN: 152342 Hom.: 202 Cov.: 33 AF XY: 0.0453 AC XY: 3378 AN XY: 74492

Gnomad4 AFR AF: 0.0674

Gnomad4 AMR AF: 0.0364

Gnomad4 ASJ AF: 0.0288

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0128

Gnomad4 FIN AF: 0.0490

Gnomad4 NFE AF: 0.0401

Gnomad4 OTH AF: 0.0450

Alfa AF: 0.0427 Hom.: 181

Bravo AF: 0.0469

Asia WGS AF: 0.0190 AC: 67 AN: 3478

EpiCase AF: 0.0411

EpiControl AF: 0.0422

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

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

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 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 specified Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	1.9
DANN	Benign	0.55

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: rs17101704; hg19: chr14-64634067;