rs11847087

Variant names:

• chr14-64053302-A-G
• rs11847087
• NM_182914.3:c.9389A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182914.3(SYNE2):​c.9389A>G​(p.Asn3130Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0427 in 1,608,316 control chromosomes in the GnomAD database, including 2,162 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.070 (585 hom., cov: 33)
  • Exomes 𝑓: 0.040 (1577 hom.)
• Consequence: SYNE2 NM_182914.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.891
• Publications: 16 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013741553).
• BP6: Variant 14-64053302-A-G is Benign according to our data. Variant chr14-64053302-A-G is described in ClinVar as Benign. ClinVar VariationId is 130519.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.151 is higher than 0.05.

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.9389A>G	p.Asn3130Ser	missense	Exon 48 of 116	NP_878918.2	Q8WXH0-2
	SYNE2	NM_015180.6		c.9389A>G	p.Asn3130Ser	missense	Exon 48 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.9389A>G	p.Asn3130Ser	missense	Exon 48 of 116	ENSP00000450831.2	Q8WXH0-2
	SYNE2	ENST00000344113.8	TSL:1	c.9389A>G	p.Asn3130Ser	missense	Exon 48 of 115	ENSP00000341781.4	Q8WXH0-1
	SYNE2	ENST00000358025.7	TSL:5	c.9389A>G	p.Asn3130Ser	missense	Exon 48 of 116	ENSP00000350719.3	Q8WXH0-2

Frequencies

GnomAD3 genomes AF: 0.0699 AC: 10642 AN: 152158 Hom.: 577 Cov.: 33

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.0451

Gnomad ASJ AF: 0.0631

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00828

Gnomad FIN AF: 0.0267

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0406

Gnomad OTH AF: 0.0641

GnomAD2 exomes AF: 0.0404 AC: 9861 AN: 244102 AF XY: 0.0381

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.0305

Gnomad ASJ exome AF: 0.0659

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0283

Gnomad NFE exome AF: 0.0423

Gnomad OTH exome AF: 0.0494

GnomAD4 exome AF: 0.0399 AC: 58062 AN: 1456040 Hom.: 1577 Cov.: 37 AF XY: 0.0389 AC XY: 28155 AN XY: 723852

African (AFR) AF: 0.161 AC: 5305 AN: 32996

American (AMR) AF: 0.0328 AC: 1429 AN: 43620

Ashkenazi Jewish (ASJ) AF: 0.0613 AC: 1593 AN: 26004

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00890 AC: 749 AN: 84142

European-Finnish (FIN) AF: 0.0256 AC: 1366 AN: 53340

Middle Eastern (MID) AF: 0.0758 AC: 436 AN: 5752

European-Non Finnish (NFE) AF: 0.0401 AC: 44477 AN: 1110406

Other (OTH) AF: 0.0450 AC: 2707 AN: 60128

GnomAD4 genome AF: 0.0701 AC: 10673 AN: 152276 Hom.: 585 Cov.: 33 AF XY: 0.0687 AC XY: 5113 AN XY: 74454

African (AFR) AF: 0.154 AC: 6415 AN: 41542

American (AMR) AF: 0.0450 AC: 688 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0631 AC: 219 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00829 AC: 40 AN: 4828

European-Finnish (FIN) AF: 0.0267 AC: 284 AN: 10618

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0406 AC: 2765 AN: 68024

Other (OTH) AF: 0.0639 AC: 135 AN: 2114

Alfa AF: 0.0504 Hom.: 1271

Bravo AF: 0.0759

TwinsUK AF: 0.0369 AC: 137

ALSPAC AF: 0.0420 AC: 162

ESP6500AA AF: 0.144 AC: 522

ESP6500EA AF: 0.0406 AC: 330

ExAC AF: 0.0418 AC: 5043

Asia WGS AF: 0.0180 AC: 64 AN: 3478

EpiCase AF: 0.0429

EpiControl AF: 0.0439

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Emery-Dreifuss muscular dystrophy 5, autosomal dominant (2)
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	SYNE2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	6.8
DANN	Uncertain	0.98
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.89
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.031
Sift	Benign	0.21	T
Sift4G	Benign	0.21	T
Polyphen		0.021	B
Vest4		0.13
MPC		0.043
ClinPred		0.0097	T
GERP RS		3.0
Varity_R		0.029
gMVP		0.15
Mutation Taster		=295/5	polymorphism (auto)

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: rs11847087; hg19: chr14-64520020;