rs9944035

chr14-63981058-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182914.3(SYNE2):c.1721T>C(p.Ile574Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0776 in 1,593,248 control chromosomes in the GnomAD database, including 5,821 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (699 hom., cov: 32)
  • Exomes 𝑓: 0.076 (5122 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.30

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016518831).
• BP6: Variant 14-63981058-T-C is Benign according to our data. Variant chr14-63981058-T-C is described in ClinVar as [Benign]. Clinvar id is 130486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-63981058-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.163 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNE2	NM_182914.3	c.1721T>C	p.Ile574Thr	missense_variant	16/116	ENST00000555002.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNE2	ENST00000555002.6	c.1721T>C	p.Ile574Thr	missense_variant	16/116	1	NM_182914.3	P4

Frequencies

GnomAD3 genomes AF: 0.0920 AC: 13987 AN: 152034 Hom.: 700 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.00879

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.0790

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0680

Gnomad OTH AF: 0.105

GnomAD3 exomes AF: 0.101 AC: 25062 AN: 249116 Hom.: 1496 AF XY: 0.103 AC XY: 13861 AN XY: 135156

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.125

Gnomad ASJ exome AF: 0.147

Gnomad EAS exome AF: 0.119

Gnomad SAS exome AF: 0.163

Gnomad FIN exome AF: 0.0815

Gnomad NFE exome AF: 0.0712

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.0761 AC: 109645 AN: 1441096 Hom.: 5122 Cov.: 29 AF XY: 0.0788 AC XY: 56618 AN XY: 718200

Gnomad4 AFR exome AF: 0.113

Gnomad4 AMR exome AF: 0.125

Gnomad4 ASJ exome AF: 0.149

Gnomad4 EAS exome AF: 0.110

Gnomad4 SAS exome AF: 0.159

Gnomad4 FIN exome AF: 0.0826

Gnomad4 NFE exome AF: 0.0622

Gnomad4 OTH exome AF: 0.0889

GnomAD4 genome AF: 0.0919 AC: 13985 AN: 152152 Hom.: 699 Cov.: 32 AF XY: 0.0951 AC XY: 7071 AN XY: 74388

Gnomad4 AFR AF: 0.112

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.135

Gnomad4 EAS AF: 0.108

Gnomad4 SAS AF: 0.173

Gnomad4 FIN AF: 0.0790

Gnomad4 NFE AF: 0.0680

Gnomad4 OTH AF: 0.102

Alfa AF: 0.0808 Hom.: 1349

Bravo AF: 0.0941

TwinsUK AF: 0.0628 AC: 233

ALSPAC AF: 0.0571 AC: 220

ESP6500AA AF: 0.106 AC: 381

ESP6500EA AF: 0.0705 AC: 574

ExAC AF: 0.0992 AC: 11986

Asia WGS AF: 0.131 AC: 454 AN: 3476

EpiCase AF: 0.0823

EpiControl AF: 0.0841

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 29, 2015	- -
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. -

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

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Invitae	Jan 31, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	19
Dann	Benign	0.47
Eigen	Benign	0.13
Eigen_PC	Benign	0.048
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.73	T;T;T;T
MetaRNN	Benign	0.0017	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;.;L;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.5	D;.;D;D
REVEL	Benign	0.15
Sift	Benign	0.040	D;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.95	P;.;P;.
Vest4		0.34
MPC		0.069
ClinPred		0.038	T
GERP RS		5.6
Varity_R		0.11
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs9944035; hg19: chr14-64447776; COSMIC: COSV59940280;