rs116597541

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000555002.6(SYNE2):c.5187T>A(p.His1729Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,614,140 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0084 ( 11 hom., cov: 32)

Exomes 𝑓: 0.00082 ( 12 hom. )

Consequence

SYNE2
ENST00000555002.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.37

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020218194).

BP6

Variant 14-64021350-T-A is Benign according to our data. Variant chr14-64021350-T-A is described in ClinVar as [Benign]. Clinvar id is 313513.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00835 (1272/152296) while in subpopulation AFR AF= 0.0289 (1200/41562). AF 95% confidence interval is 0.0275. There are 11 homozygotes in gnomad4. There are 591 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1272 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE2	NM_182914.3 linkuse as main transcript	c.5187T>A	p.His1729Gln	missense_variant	36/116	ENST00000555002.6	NP_878918.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNE2	ENST00000555002.6 linkuse as main transcript	c.5187T>A	p.His1729Gln	missense_variant	36/116	1	NM_182914.3	ENSP00000450831	P4	Q8WXH0-2

Frequencies

GnomAD3 genomes

AF:

0.00836

AC:

1272

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00622

GnomAD3 exomes

AF:

0.00209

AC:

521

AN:

249330

Hom.:

AF XY:

0.00163

AC XY:

220

AN XY:

135272

show subpopulations

Gnomad AFR exome

AF:

0.0292

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.000820

AC:

1199

AN:

1461844

Hom.:

Cov.:

AF XY:

0.000708

AC XY:

515

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.0277

Gnomad4 AMR exome

AF:

0.00152

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000791

Gnomad4 OTH exome

AF:

0.00164

GnomAD4 genome

AF:

0.00835

AC:

1272

AN:

152296

Hom.:

Cov.:

AF XY:

0.00794

AC XY:

591

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0289

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00616

Alfa

AF:

0.000446

Hom.:

Bravo

AF:

0.00931

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0298

AC:

115

ESP6500EA

AF:

0.000121

AC:

ExAC

AF:

0.00268

AC:

324

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 13, 2016

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.0090

DANN

Benign

0.66

DEOGEN2

Benign

0.059

.;T;T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.48

T;T;T;T

MetaRNN

Benign

0.0020

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

N;.;N;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-3.1

D;.;D;D

REVEL

Benign

0.035

Sift

Benign

0.19

T;.;T;T

Sift4G

Benign

0.47

T;T;T;T

Polyphen

0.0010

B;.;B;.

Vest4

0.13

MutPred

0.30

Gain of disorder (P = 0.0473);Gain of disorder (P = 0.0473);Gain of disorder (P = 0.0473);Gain of disorder (P = 0.0473);

MVP

0.15

MPC

0.049

ClinPred

0.0039

GERP RS

-6.5

Varity_R

0.089

gMVP

0.070

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over