14-64081575-G-A

Variant names:

• chr14-64081575-G-A
• rs138514054
• NM_182914.3:c.11479G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_182914.3(SYNE2):​c.11479G>A​(p.Val3827Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. V3827L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.61
• Publications: 5 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14320362).

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.11479G>A	p.Val3827Met	missense	Exon 57 of 116	NP_878918.2
	SYNE2	NM_015180.6		c.11479G>A	p.Val3827Met	missense	Exon 57 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.11479G>A	p.Val3827Met	missense	Exon 57 of 116	ENSP00000450831.2
	SYNE2	ENST00000344113.8	TSL:1	c.11479G>A	p.Val3827Met	missense	Exon 57 of 115	ENSP00000341781.4
	SYNE2	ENST00000394768.6	TSL:1	n.943G>A		non_coding_transcript_exon	Exon 4 of 63

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Benign	0.82
DEOGEN2	Benign	0.0069	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.6
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.48	N
REVEL	Benign	0.067
Sift	Benign	0.16	T
Sift4G	Uncertain	0.017	D
Polyphen		0.0080	B
Vest4		0.24
MutPred		0.36		Gain of disorder (P = 0.0345)
MVP		0.21
MPC		0.051
ClinPred		0.51	D
GERP RS		5.6
Varity_R		0.028
gMVP		0.069
Mutation Taster		=91/9	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: rs138514054; hg19: chr14-64548293;