rs201176149

Variant names:

• chr14-63976588-A-G
• rs201176149
• NM_182914.3:c.1154A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_182914.3(SYNE2):​c.1154A>G​(p.Asn385Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000352 in 1,608,268 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 6.06
• Publications: 1 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• left ventricular noncompaction

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009871334).
• BP6: Variant 14-63976588-A-G is Benign according to our data. Variant chr14-63976588-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 283981.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000413 (61/147598) while in subpopulation AMR AF = 0.000612 (9/14696). AF 95% confidence interval is 0.000319. There are 0 homozygotes in GnomAd4. There are 29 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High AC in GnomAd4 at 61 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.1154A>G	p.Asn385Ser	missense	Exon 12 of 116	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.1154A>G	p.Asn385Ser	missense	Exon 12 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.1154A>G	p.Asn385Ser	missense	Exon 12 of 116	ENSP00000450831.2	Q8WXH0-2
	SYNE2	ENST00000344113.8	TSL:1	c.1154A>G	p.Asn385Ser	missense	Exon 12 of 115	ENSP00000341781.4	Q8WXH0-1
	SYNE2	ENST00000358025.7	TSL:5	c.1154A>G	p.Asn385Ser	missense	Exon 12 of 116	ENSP00000350719.3	Q8WXH0-2

Frequencies

GnomAD3 genomes AF: 0.000407 AC: 60 AN: 147516 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000613

Gnomad ASJ AF: 0.00636

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000385

Gnomad OTH AF: 0.000986

GnomAD2 exomes AF: 0.000334 AC: 83 AN: 248570 AF XY: 0.000341

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000435

Gnomad ASJ exome AF: 0.00250

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000293

Gnomad OTH exome AF: 0.00150

GnomAD4 exome AF: 0.000346 AC: 505 AN: 1460670 Hom.: 0 Cov.: 37 AF XY: 0.000322 AC XY: 234 AN XY: 726630

African (AFR) AF: 0.0000299 AC: 1 AN: 33404

American (AMR) AF: 0.000448 AC: 20 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00387 AC: 101 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86068

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.000307 AC: 341 AN: 1111342

Other (OTH) AF: 0.000647 AC: 39 AN: 60310

GnomAD4 genome AF: 0.000413 AC: 61 AN: 147598 Hom.: 0 Cov.: 28 AF XY: 0.000404 AC XY: 29 AN XY: 71788

African (AFR) AF: 0.00 AC: 0 AN: 39452

American (AMR) AF: 0.000612 AC: 9 AN: 14696

Ashkenazi Jewish (ASJ) AF: 0.00636 AC: 22 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5064

South Asian (SAS) AF: 0.000426 AC: 2 AN: 4698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 280

European-Non Finnish (NFE) AF: 0.000385 AC: 26 AN: 67470

Other (OTH) AF: 0.000978 AC: 2 AN: 2046

Alfa AF: 0.000512 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000489 AC: 4

ExAC AF: 0.000240 AC: 29

EpiCase AF: 0.000654

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Emery-Dreifuss muscular dystrophy 5, autosomal dominant (3)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0099	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.1
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.10
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.016	D
Polyphen		0.017	B
Vest4		0.27
MVP		0.32
MPC		0.061
ClinPred		0.048	T
GERP RS		4.0
Varity_R		0.090
gMVP		0.095
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: rs201176149; hg19: chr14-64443306;