Variant chr14-64016605-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The ENST00000555002.6(SYNE2):c.4861A>C(p.Asn1621His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000623 in 1,445,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

SYNE2
ENST00000555002.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.75

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 Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.34311083).

BS2

High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNE2	NM_182914.3 linkuse as main transcript	c.4861A>C	p.Asn1621His	missense_variant	33/116	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.4861A>C	p.Asn1621His	missense_variant	33/116	1	NM_182914.3	ENSP00000450831	P4	Q8WXH0-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000412

AC:

AN:

242658

Hom.:

AF XY:

0.00000760

AC XY:

AN XY:

131522

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000901

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000623

AC:

AN:

1445146

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

719120

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000817

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 06, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 12, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 538343). This variant has not been reported in the literature in individuals affected with SYNE2-related conditions. This variant is present in population databases (rs746284520, gnomAD 0.0009%). This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 1621 of the SYNE2 protein (p.Asn1621His). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.016

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.031

.;T;T;T

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.86

D;D;D;D

M_CAP

Benign

0.078

MetaRNN

Benign

0.34

T;T;T;T

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.1

M;.;M;.

MutationTaster

Benign

1.0

D;N;N;N

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.3

N;.;N;N

REVEL

Benign

0.15

Sift

Uncertain

0.013

D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.94

P;.;P;.

Vest4

0.68

MutPred

0.42

Loss of catalytic residue at N1621 (P = 0.0787);Loss of catalytic residue at N1621 (P = 0.0787);Loss of catalytic residue at N1621 (P = 0.0787);Loss of catalytic residue at N1621 (P = 0.0787);

MVP

0.46

MPC

0.33

ClinPred

0.73

GERP RS

4.6

Varity_R

0.16

gMVP

0.21

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