rs149617373

chr14-64142030-A-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.15248A>G(p.Asp5083Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,614,036 control chromosomes in the GnomAD database, including 3 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 0.00082 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.51

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=0.013123214).
• BP6: Variant 14-64142030-A-G is Benign according to our data. Variant chr14-64142030-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 198953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64142030-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000821 (125/152252) while in subpopulation NFE AF= 0.00138 (94/68020). AF 95% confidence interval is 0.00116. There are 1 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 125 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.15248A>G	p.Asp5083Gly	missense_variant	82/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.15248A>G	p.Asp5083Gly	missense_variant	82/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.000822 AC: 125 AN: 152136 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000738 AC: 185 AN: 250844 Hom.: 0 AF XY: 0.000642 AC XY: 87 AN XY: 135568

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00102

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00113 AC: 1655 AN: 1461784 Hom.: 2 Cov.: 32 AF XY: 0.00110 AC XY: 803 AN XY: 727206

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00112

Gnomad4 NFE exome AF: 0.00134

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.000821 AC: 125 AN: 152252 Hom.: 1 Cov.: 32 AF XY: 0.000779 AC XY: 58 AN XY: 74450

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00138

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.00110 Hom.: 0

Bravo AF: 0.000676

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000725 AC: 88

EpiCase AF: 0.00115

EpiControl AF: 0.00119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SYNE2: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 04, 2019	- -

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

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. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 07, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 18, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	9.3
Dann	Benign	0.96
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.75	T;T;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.013	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L;.;L;.;.
MutationTaster	Benign	0.53	N;N;N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-4.6	D;.;D;D;D
REVEL	Benign	0.051
Sift	Benign	0.062	T;.;T;T;T
Sift4G	Benign	0.16	T;T;T;T;T
Polyphen		0.0060	B;.;B;B;.
Vest4		0.10
MVP		0.27
MPC		0.060
ClinPred		0.020	T
GERP RS		0.85
Varity_R		0.081
gMVP		0.12

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: rs149617373; hg19: chr14-64608748;