rs753039223

Variant names:

• chr14-63977995-A-G
• rs753039223
• NM_182914.3:c.1384A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BS1_Supporting BS2

The NM_182914.3(SYNE2):​c.1384A>G​(p.Lys462Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,611,204 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: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.39
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26993328).
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000192 (28/1459018) while in subpopulation NFE AF = 0.0000243 (27/1109434). AF 95% confidence interval is 0.0000167. There are 0 homozygotes in GnomAdExome4. There are 16 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 28 AD,Unknown gene.

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.1384A>G	p.Lys462Glu	missense	Exon 13 of 116	NP_878918.2
	SYNE2	NM_015180.6		c.1384A>G	p.Lys462Glu	missense	Exon 13 of 115	NP_055995.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	ENST00000555002.6	TSL:1 MANE Select	c.1384A>G	p.Lys462Glu	missense	Exon 13 of 116	ENSP00000450831.2
	SYNE2	ENST00000344113.8	TSL:1	c.1384A>G	p.Lys462Glu	missense	Exon 13 of 115	ENSP00000341781.4
	SYNE2	ENST00000358025.7	TSL:5	c.1384A>G	p.Lys462Glu	missense	Exon 13 of 116	ENSP00000350719.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 249322 AF XY: 0.0000222

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1459018 Hom.: 0 Cov.: 29 AF XY: 0.0000220 AC XY: 16 AN XY: 726058

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.00 AC: 0 AN: 86202

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000243 AC: 27 AN: 1109434

Other (OTH) AF: 0.0000166 AC: 1 AN: 60306

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74348

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000312 Hom.: 0

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00000827 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Emery-Dreifuss muscular dystrophy 5, autosomal dominant Uncertain:1

Apr 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 462 of the SYNE2 protein (p.Lys462Glu). This variant is present in population databases (rs753039223, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with SYNE2-related conditions. ClinVar contains an entry for this variant (Variation ID: 538348). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.4
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.21
Sift	Uncertain	0.0080	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.41
MutPred		0.33		Loss of ubiquitination at K462 (P = 0.0127)
MVP		0.62
MPC		0.25
ClinPred		0.67	D
GERP RS		6.1
Varity_R		0.15
gMVP		0.30
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs753039223; hg19: chr14-64444713;