rs142660236

Positions:

• chr14-64158626-T-C

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.15794T>C​(p.Val5265Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0139 in 1,613,822 control chromosomes in the GnomAD database, including 196 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (16 hom., cov: 32)
  • Exomes 𝑓: 0.014 (180 hom.)
• Consequence: SYNE2 NM_182914.3 missense, splice_region
• Scores: Splicing: ADA: 0.6095
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.81

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=0.0029333234).
• BP6: Variant 14-64158626-T-C is Benign according to our data. Variant chr14-64158626-T-C is described in ClinVar as [Benign]. Clinvar id is 130481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-64158626-T-C is described in Lovd as [Benign]. Variant chr14-64158626-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0121 (1847/152276) while in subpopulation NFE AF= 0.0168 (1140/68022). AF 95% confidence interval is 0.016. There are 16 homozygotes in gnomad4. There are 940 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1847 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.15794T>C	p.Val5265Ala	missense_variant, splice_region_variant	86/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.15794T>C	p.Val5265Ala	missense_variant, splice_region_variant	86/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1849 AN: 152158 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.00287

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.0429

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.0350

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.0138 AC: 3454 AN: 250958 Hom.: 40 AF XY: 0.0149 AC XY: 2016 AN XY: 135646

Gnomad AFR exome AF: 0.00222

Gnomad AMR exome AF: 0.0124

Gnomad ASJ exome AF: 0.0441

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0136

Gnomad FIN exome AF: 0.0103

Gnomad NFE exome AF: 0.0158

Gnomad OTH exome AF: 0.0200

GnomAD4 exome AF: 0.0141 AC: 20596 AN: 1461546 Hom.: 180 Cov.: 32 AF XY: 0.0144 AC XY: 10492 AN XY: 727082

Gnomad4 AFR exome AF: 0.00287

Gnomad4 AMR exome AF: 0.0130

Gnomad4 ASJ exome AF: 0.0436

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0141

Gnomad4 FIN exome AF: 0.00952

Gnomad4 NFE exome AF: 0.0143

Gnomad4 OTH exome AF: 0.0157

GnomAD4 genome AF: 0.0121 AC: 1847 AN: 152276 Hom.: 16 Cov.: 32 AF XY: 0.0126 AC XY: 940 AN XY: 74450

Gnomad4 AFR AF: 0.00286

Gnomad4 AMR AF: 0.0141

Gnomad4 ASJ AF: 0.0429

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0139

Gnomad4 FIN AF: 0.0106

Gnomad4 NFE AF: 0.0168

Gnomad4 OTH AF: 0.0151

Alfa AF: 0.0164 Hom.: 39

Bravo AF: 0.0117

TwinsUK AF: 0.0127 AC: 47

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0170 AC: 146

ExAC AF: 0.0134 AC: 1624

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0174

EpiControl AF: 0.0197

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jul 28, 2017	- -

not specified Benign:2

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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.069	.;T;T;T;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	T;T;T;T;T
MetaRNN	Benign	0.0029	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;N
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.1	D;.;D;D;D
REVEL	Benign	0.085
Sift	Benign	0.031	D;.;D;D;D
Sift4G	Uncertain	0.052	T;T;T;T;T
Polyphen		0.41	B;.;B;P;.
Vest4		0.52
MPC		0.18
ClinPred		0.013	T
GERP RS		5.8
Varity_R		0.13
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.61
dbscSNV1_RF	Benign	0.57
SpliceAI score (max)		0.020		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: rs142660236; hg19: chr14-64625344;