rs781375790

Variant names:

• chr14-63909176-G-A
• rs781375790
• NM_182914.3:c.28G>A

Your query was ambiguous. Multiple possible variants found:

• chr14-63909176-G-A
• chr14-63909176-G-C
• chr14-63909176-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_182914.3(SYNE2):​c.28G>A​(p.Glu10Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E10Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.33
• Publications: 3 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
• left ventricular noncompaction

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• Emery-Dreifuss muscular dystrophy 5, autosomal dominant

  Inheritance: Unknown, AD Classification: LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.13657874).
• BS2: High AC in GnomAdExome4 at 7 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	NM_182914.3	MANE Select	c.28G>A	p.Glu10Lys	missense	Exon 2 of 116	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.28G>A	p.Glu10Lys	missense	Exon 2 of 115	NP_055995.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNE2	ENST00000555002.6	TSL:1 MANE Select	c.28G>A	p.Glu10Lys	missense	Exon 2 of 116	ENSP00000450831.2	Q8WXH0-2
	SYNE2	ENST00000344113.8	TSL:1	c.28G>A	p.Glu10Lys	missense	Exon 2 of 115	ENSP00000341781.4	Q8WXH0-1
	SYNE2	ENST00000341472.9	TSL:1	c.28G>A	p.Glu10Lys	missense	Exon 2 of 9	ENSP00000344528.5	Q8WXH0-8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249234 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461356 Hom.: 0 Cov.: 29 AF XY: 0.00000550 AC XY: 4 AN XY: 727030

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111580

Other (OTH) AF: 0.0000166 AC: 1 AN: 60374

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Emery-Dreifuss muscular dystrophy 5, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.3
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.20
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.14	T
Polyphen		0.45	P
Vest4		0.18
MutPred		0.30		Gain of ubiquitination at E10 (P = 0.0037)
MVP		0.69
MPC		0.053
ClinPred		0.15	T
GERP RS		4.5
PromoterAI		-0.088	Neutral
Varity_R		0.17
gMVP		0.29
Mutation Taster		=87/13	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: rs781375790; hg19: chr14-64375894; COSMIC: COSV58359837;