Genetic Variant NM_182914.3:c.2827G>A (chr14-63995089-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_182914.3(SYNE2):c.2827G>A(p.Asp943Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000703 in 1,422,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D943Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

SYNE2
NM_182914.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.48

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

autosomal dominant Emery-Dreifuss muscular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Emery-Dreifuss muscular dystrophy 5, autosomal dominant
Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Ambry Genetics
left ventricular noncompaction
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

SYNE2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31064206).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182914.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	NM_182914.3	MANE Select	c.2827G>A	p.Asp943Asn	missense	Exon 23 of 116	NP_878918.2
	SYNE2	NM_015180.6		c.2827G>A	p.Asp943Asn	missense	Exon 23 of 115	NP_055995.4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SYNE2	ENST00000555002.6	TSL:1 MANE Select	c.2827G>A	p.Asp943Asn	missense	Exon 23 of 116	ENSP00000450831.2
SYNE2	ENST00000344113.8	TSL:1	c.2827G>A	p.Asp943Asn	missense	Exon 23 of 115	ENSP00000341781.4
SYNE2	ENST00000358025.7	TSL:5	c.2827G>A	p.Asp943Asn	missense	Exon 23 of 116	ENSP00000350719.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.03e-7

AC:

AN:

1422872

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

707756

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31964

American (AMR)

AF:

0.00

AC:

AN:

41948

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25426

East Asian (EAS)

AF:

0.0000255

AC:

AN:

39188

South Asian (SAS)

AF:

0.00

AC:

AN:

81962

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5622

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1085500

Other (OTH)

AF:

0.00

AC:

AN:

58848

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.036

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.042

MetaRNN

Benign

0.31

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.2

PhyloP100

4.5

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.13

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.012

Polyphen

0.95

Vest4

0.24

MutPred

0.32

Gain of MoRF binding (P = 0.0435)

MVP

0.55

MPC

0.30

ClinPred

0.97

GERP RS

4.9

Varity_R

0.25

gMVP

0.097

Mutation Taster

=93/7

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over